Triazole compounds suitable for treating disorders that respond to modulation of the dopamine d3 receptor

ABSTRACT

The invention relates to compounds of formula (I), wherein n is 1 or 2, Ar is a C-bound 1,2,4-triazol radical which carries a radical R 1  on the remaining carbon atom and a radical R 1a  on one of the nitrogen atoms; R 1  is hydrogen, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, C 1 -C 4  alkoxymethyl, fluorinated C 1 -C 6  alkyl, fluorinated C 3 -C 6  cycloalkyl, fluorinated C 1 -C 4  alkoxymethyl, or optionally substituted phenyl or 5- or 6-membered heteroaryl; R 1a  is hydrogen or C 1 -C 4  alkyl; and R 2  is C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, fluorinated C 1 -C 6  alkyl or fluorinated C 3 -C 6  cycloalkyl; and to the physiologically tolerated acid addition salts of there compounds. The invention also relates to a pharmaceutically composition that comprises at least one triazole compound of the formula (I) and/or at least one physiologically tolerated acid addition salt thereof, and further to a method for treating disorders that respond beneficially to dopamine D 3  receptor antagonists or dopamine D 3  agonists, said method comprising administering an effective amount of at least one triazole compound or physiologically tolerated acid addition salt of the formula (I) to a subject in need thereof.

BACKGROUND OF THE INVENTION

The present invention relates to novel triazole compounds. The compoundspossess valuable therapeutic properties and are suitable, in particular,for treating diseases that respond to modulation of the dopamine D₃receptor.

Neurons obtain their information by way of G protein-coupled receptors,inter alia. A large number of substances exert their effect by way ofthese receptors. One of them is dopamine. Confirmed findings exist withregard to the presence of dopamine and its physiological function as aneurotransmitter. Disorders in the dopaminergic transmitter systemresult in diseases of the central nervous system which include, forexample, schizophrenia, depression and Parkinson's disease. Thesediseases, and others, are treated with drugs which interact with thedopamine receptors.

Up until 1990, two subtypes of dopamine receptor had been clearlydefined pharmacologically, termed D₁ and D₂ receptors. More recently, athird subtype was found, namely, the D₃ receptor which appears tomediate some effects of antipsychotics and antiparkinsonians (J. C.Schwartz et al., “The Dopamine D₃ Receptor as a Target forAntipsychotics” in Novel Antipsychotic Drugs, H. Y. Meltzer, ed., RavenPress, New York 1992, pages 135-144; M. Dooley et al., Drugs and Aging1998, 12:495-514; J. N. Joyce, Pharmacology and Therapeutics 2001,90:231-59, “The Dopamine D₃ Receptor as a Therapeutic Target forAntipsychotic and Antiparkinsonian Drugs”). Since then, the dopaminereceptors have been divided into two families. On the one hand, there isthe D₂ group, consisting of D₂, D₃ and D₄ receptors, and, on the otherhand, the D₁ group, consisting of D₁ and D₅ receptors.

Whereas D₁ and D₂ receptors are widely distributed, D₃ receptors appearto be expressed regioselectively. Thus, these receptors arepreferentially to be found in the limbic system and the projectionregions of the mesolimbic dopamine system, especially in the nucleusaccumbens, but also in other regions, such as the amygdala. Because ofthis comparatively regioselective expression, D₃ receptors are regardedas being a target having few side-effects and it is assumed that while aselective D₃ ligand would have the properties of known antipsychotics,it would not have their dopamine D₂ receptor-mediated neurologicalside-effects (P. Sokoloff et al., Arzneim. Forsch./Drug Res. 42(1):224(1992), “Localization and Function of the D₃ Dopamine Receptor”; P.Sokoloff et al., Nature, 347:146 (1990), “Molecular Cloning andCharacterization of a Novel Dopamine Receptor (D₃) as a Target forNeuroleptics”).

Triazole compounds having an affinity for the dopamine D₃ receptor havebeen described previously on various occasions, as for example inpublished PCT applications WO 96/02520, WO 99/02503, WO 00/42036, WO00/42037, WO 00/42038. Some of these compounds possess high affinitiesfor the dopamine D₃ receptor, and have therefore been proposed as beingsuitable for treating diseases of the central nervous system.Unfortunately, their selectivity towards the D₃ receptor is not alwayssatisfactory. Moreover, it has often been difficult to achieve highbrain levels with such known compounds. Consequently there is an ongoingneed to provide new compounds, which either have an improved selectivitytowards D₃ receptors or an improved pharmacological profile, such as ahigher brain plasma ratio, a higher bioavailability, favourablemetabolic behaviour such as a decreased inhibition of the mitochondrialrespiration and favourable profile regarding their interaction withcytochrome P450 isoenzymes.

SUMMARY OF THE INVENTION

It has now been found that certain triazole compounds exhibit, to asurprising and unexpected degree, highly selective binding to thedopamine D₃ receptor as well as the ability to attain high brain levels.Such compounds are those having the general formula I

wherein

-   n is 1 or 2,-   Ar is a C-bound 1,2,4-triazol radical which carries a radical R¹ on    the remaining carbon atom and a radical R^(1a) on one of the    nitrogen atoms; wherein-   R¹ is hydrogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₄ alkoxymethyl,    fluorinated C₁-C₆ alkyl, fluorinated C₃-C₆ cycloalkyl, fluorinated    C₁-C₄ alkoxymethyl,    -   phenyl or 5- or 6-membered heteroaryl, wherein phenyl and        heteroaryl may be un-substituted or substituted by 1, 2, 3 or 4        radicals R^(a) selected independently of each other from        halogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₄        alkoxy-C₁-C₄-alkyl, fluorinated C₁-C₄ alkyl, CN, NO₂, OR³,        NR³R⁴, C(O)NR³R⁴, O—C(O)NR³R⁴, SO₂NR³R⁴, COOR⁵, SR⁶, SOR⁶,        SO₂R⁶, O—C(O)R⁷, COR⁷ or C₃-C₅ cycloalkylmethyl, wherein phenyl        and heteroaryl may also carry a phenyl group or an aromatic 5-        or 6-membered C-bound heteroaromatic radical, comprising 1        nitrogen atom as ring member and 0, 1, 2 or 3 further        heteroatoms, independently of each other, selected from O, S and        N, wherein the last two mentioned radicals may carry 1, 2, 3 or        4 of the aforementioned radicals R^(a)-   R^(1a) is hydrogen or C₁-C₄-alkyl-   R² is C₁-C₆ alkyl, C₃-C₆ cycloalkyl, fluorinated C₁-C₆ alkyl or    fluorinated C₃-C₆ cycloalkyl-   R³, R⁴, R⁵, R⁶, and R⁷ independent of each other are H, C₁-C₆ alkyl,    optionally substituted with OH, C₁-C₄ alkoxy or phenyl, C₁-C₄    haloalkyl or phenyl, which may carry 1, 2 or 3 radicals selected    from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy,    NR^(3a)R^(4a), CN, C₁-C₂ fluoroalkyl and halogen, wherein R^(3a) and    R^(4a) are independent of each other H, C₁-C₆ alkyl, optionally    substituted with OH, C₁-C₄ alkoxy or phenyl, C₁-C₄ haloalkyl or    phenyl, which may carry 1, 2 or 3 radicals selected from the group    consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, amino, NH(C₁-C₄ alkyl) and    N(C₁-C₄ alkyl)₂, R⁴ may also be a radical COR^(S), wherein R⁸ is    hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxy or phenyl, which may carry 1, 2    or 3 radicals selected from the group consisting of C₁-C₆ alkyl,    C₁-C₆ alkoxy, NR³R⁴, CN, C₁-C₂ fluoroalkyl and halogen, R³ and R⁴    may together with the nitrogen atom to which they are bound form a    N-bound 5 or 6 membered saturated heterocyle, which may comprise an    oxygen atom or an additional nitrogen atom as a ring member and    which may carry 1, 2, 3 or 4 C₁-C₆ alkyl groups    and the physiologically tolerated acid addition salts of these    compounds.

The present invention therefore relates to triazole compounds of thegeneral formula I and to their physiologically tolerated acid additionsalts.

The present invention also relates to a pharmaceutical composition whichcomprises at least one triazole compound of the formula I and/or atleast one physiologically tolerated acid addition salt of I, whereappropriate together with physiologically acceptable carriers and/orauxiliary substances.

The present invention also relates to a method for treating disorderswhich respond to influencing by dopamine D₃ receptor antagonists ordopamine D₃ agonists, said method comprising administering an effectiveamount of at least one triazole compound of the formula I and/or atleast one physiologically tolerated acid addition salt of I to a subjectin need thereof.

DETAILED DESCRIPTION OF THE INVENTION

The diseases which respond to the influence of dopamine D₃ receptorantagonists or agonists include disorders and diseases of the centralnervous system, in particular affective disturbances, neuroticdisturbances, stress disturbances and somatoform disturbances andpsychoses, and especially schizophrenia, depression, bipolar disorder,substance abuse, dementia, major depressive disorder, anxiety, autism,attention deficit disorder with or without hyperactivity and personalitydisorder. In addition, D₃-mediated diseases may include disturbances ofkidney function, in particular kidney function disturbances which arecaused by diabetes mellitus (see WO 00/67847).

According to the invention, one or more compounds of the general formulaI having the meanings mentioned at the outset can be used for treatingthe above-mentioned indications. Provided the compounds of the formula Ipossess one or more centers of asymmetry, it is also possible to useenantiomeric mixtures, in particular racemates, diastereomeric mixturesand tautomeric mixtures; preferred, however, are the respectiveessentially pure enantiomers, diastereomers and tautomers.

It is likewise possible to use physiologically tolerated salts of thecompounds of the formula I, especially acid addition salts withphysiologically tolerated acids. Examples of suitable physiologicallytolerated organic and inorganic acids are hydrochloric acid, hydrobromicacid, phosphoric acid, nitric acid, sulfuric acid, organic sulfonicacids having from 1 to 12 carbon atoms, e.g. C₁-C₄-alkylsulfonic acidssuch as methanesulfonic acid, cycloaliphatic sulfonic acids such asS-(+)-10-camphorsulfonic acids and aromatic sulfonic acids such asbenzenesulfonic acid and toluenesulfonic acid, di- and tricarboxylicacids and hydroxycarboxylic acids having from 2 to 10 carbon atoms suchas oxalic acid, malonic acid, maleic acid, fumaric acid, mucic acid,lactic acid, tartaric acid, citric acid, glycolic acid and adipic acid,as well as cis- and trans-cinnamic acid, furoic acid and benzoic acid.Other utilizable acids are described in Fortschritte derArzneimittelforschung [Advances in Drug Research], Volume 10, pages 224ff., Birkhäuser Verlag, Base1 and Stuttgart, 1966. The physiologicallytolerated salts of compounds of the formula I may be present as themono-, bis-, tris- and tetrakis-salts, that is, they may contain 1, 2, 3or 4 of the aforementioned acid molecules per molecule of formula I. Theacid molecules may be present in their acidic form or as an anion.

As used herein, C₁-C₆ alkyl is a straight-chain or branched alkyl grouphaving 1, 2, 3, 4, 5 or 6 carbon atoms. Examples of such a group aremethyl, ethyl,n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl,tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 1-ethylpropyl,n-hexyl.

As used herein “5- or 6-membered aromatic radicals” comprise monocyclicaromatic radicals which comprise 1, 2, 3 or 4 heteroatoms as ringmembers which are selected, independently of each other from O, S and N.Examples are pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, imidazolyl,pyrrolyl, pyrazolyl, thienyl, furanyl, oxazolyl, thiazolyl, isoxazolyl,tetrazolyl, thiadiazolyl and triazolyl.

A first embodiment of the invention relates to compounds of the formulaI, wherein Ar is a radical of the formula Ar-1,

wherein # denotes the binding position to the sulfur atom of the groupS(O)_(n) and wherein R¹ is as defined herein.

A second embodiment of the invention relates to compounds of the formulaI, wherein Ar is a radical of the formula Ar-2

wherein # denotes the binding position to the sulfur atom of the groupS(O)_(n) and wherein R¹ and R^(1a) are as defined herein.

A third embodiment of the invention relates to compounds of the formulaI, wherein Ar is a radical of the formula Ar-3

wherein # denotes the binding position to the sulfur atom of the groupS(O)_(n) and wherein R¹ and R^(1a) are as defined herein.

R^(1a) is preferably hydrogen or methyl, in particular methyl.

With regard to using the compounds according to the invention asdopamine D₃ receptor ligands, preference is given to those compounds offormula I in which the radical R¹ is hydrogen, C₁-C₄ alkyl, C₃-C₅cycloalkyl, alkoxymethyl or trifluoromethyl, in particular hydrogen,C₁-C₄ alkyl, cyclopropyl, cyclobutyl, CH₂—OCH₃, CH₂—OCH₂H₅ ortrifluoromethyl, especially methyl, ethyl, n-propyl, isopropyl,cyclopropyl, cyclobutyl, tert-butyl or trifluoromethyl and mostpreferably hydrogen or methyl.

R² is preferably C₃-C₄ alkyl or fluorinated C₁-C₂ alkyl, in particularn-propyl, isopropyl or tert-butyl, or alternatively trifluoromethyl ordifluoromethyl. More preferable are compounds in which R² is tert-butyl,difluoromethyl or trifluoromethyl, and most preferred are those in whichR² is tert-butyl. Preferred compounds of the formula I may also carryC₃-C₄ cycloalkyl or fluorinated C₃-C₄ cycloalkyl as a radical R².

In another embodiment R¹ is optionally substituted phenyl or optionallysubstituted 5- or 6-membered hetaryl, which may be unsubstituted orsubstituted as mentioned above. Preferred substituents on phenyl and 5-or 6-membered heteroaryl comprise halogen, in particular fluorine orchlorine, C₁-C₄ alkyl, C₁-C₄ alkoxy, flurinated C₁-C₂ alkyl, andfluorinated C₁-C₂ alkoxy. Preferably the number of substituents is 0, 1or 2. Amongst the aromatic radicals preference is given to phenyl,thienyl and pyrrolyl, which are unsubstituted or substituted asmentioned above. Examples for suitable radicals comprise phenyl, 2-, 3-and 4-fluorophenyl, 2- and 3-thienyl and 1-methyl-pyrrol-2-yl.

The compounds of the present invention can e.g. be prepared from thecorresponding sulfanyl precursors of the formula II

wherein Ar and R² are as defined above, via oxidation of the thioethermoiety whereby the sulfinyl-derivatives Ia (n=1) and/or the sulfonylderivatives Ib (n=2) are obtained, depending on the amount of oxidizingagent or the reaction conditions (see scheme 1). Suitable oxidizingreagents comprise peracids such as metachloroperbenzoic acid (mCPBA)(for reaction conditions see e.g. Tetrahedron. Lett., 2001, 42 (46),8161), periodates such as sodium periodate (for reaction conditions seee.g. Can. J. Chem., 2001, 79, (8), 1238), organic peroxides andinorganic peroxides such as tert-butyl-hydroperoxide, hydrogenperoxide(for reaction conditions see e.g. J. Heterocycl. Chem., 2001, 38 (5),1035), oxone (for reaction conditions see e.g. Bioorg. Med. Chem. Lett.,2001, 11, (20), 2723), magnesium monoperoxophthalate (for reactionconditions see e.g. Synthesis, 2001, 12, 1778), and the like, with oxonebeing preferred.

The chiral sulfinyl derivatives Ia are also accessible viaenantioselective oxidation using e.g.diethyl-tartrate/tert-butyl-hydroperoxide/titan-tetraisopropoxide asdescribed in (i) J. Med. Chem., 2002, 45, 3972, hydrogenperoxide withchiral ligands bound to a solid support (see e.g. Chem. Commun. 2001,24, 2594), hydrogen peroxide in combination with a vanadate-basedcatalyst and(1S,2R)—N-(1-(2-biphenylyl)-2-OH-3-naphthylmethylidene)-1-amino-2-indanolas chiral ligand (see e.g. Synlett., 2002, 1, 161),1-(2-furyl)-1-methylethyl hydroperoxide/titanium tetraisopropoxide inthe presence of (R)- or (S)-binol (see e.g. Tetrahedron: Asymmetry,2001, 12 (20), 2775), or (S,S)- or (R,R)-diethyl tartrate/titaniumtetraisopropoxide/cumene hydroperoxide (see e.g. Nature Reviews in DrugDiscovery, 2003, 663).

Some of the compounds of the general formula II, namely the compounds ofthe formula II, wherein

-   R¹ is selected from the group consisting of C₂-C₆-alkyl, fluorinated    C₁-C₆-alkyl, C₃-C₆ cycloalkyl, C₁-C₄ alkoxymethyl, fluorinated C₃-C₆    cycloalkyl and fluorinated C₁-C₄ alkoxymethyl and-   R² is selected from the group consisting of C₁-C₆ alkyl and    fluorinated C₁-C₆ alkyl    and the physiologically tolerated acid addition salts of these    compounds are new and thus form part of the invention. They are    hereinafter referred to as compounds IIa.

A fourth embodiment of the invention relates to compounds of the formulaIIa, wherein Ar is Ar-1 as defined above.

A fifth embodiment of the invention relates to compounds of the formulaIIa, wherein Ar is Ar-2 as defined above.

A sixth embodiment of the invention relates to compounds of the formulaIIa, wherein Ar is Ar-3 as defined above.

The new compounds of the formula II (compounds IIa) and theirphysiologically tolerated acid addition salts are highly selectivetowards the dopamine D₃ receptor and provide a similar beneficialpharmacological profile as the compounds I of the invention. Thereforecompounds IIa are useful for treating disorders which respond toinfluencing by dopamine D₃ receptor ligands, such as dopamine D₃receptor antagonists or dopamine D₃ agonists.

Therefore, the present invention also relates to a pharmaceuticalcomposition which comprises at least one triazole compound IIa and/or atleast one physiologically tolerated acid addition salt of IIa, whereappropriate together with physiologically acceptable carriers and/orauxiliary substances.

The present invention also relates to a method for treating disorderswhich respond to influencing by dopamine D₃ receptor antagonists ordopamine D₃ agonists, said method comprising administering an effectiveamount of at least one triazole compound of the formula IIa and/or atleast one physiologically tolerated acid addition salt of IIa to asubject in need thereof.

In the new compounds of formula IIa R¹ is preferably C₂-C₄-alkyl,trifluoromethyl, C₃-C₅ cycloalkyl or C₁-C₄ alkoxymethyl, in particularethyl, n-propyl, isopropyl, tert.-butyl, cyclopropyl, cyclobutyl,trifluoromethyl, CH₂—OCH₃ or CH₂—OCH₂H₅.

In the new compounds of formula IIa R² is preferably C₃-C₄ alkyl orfluorinated C₁-C₂ alkyl, in particular n-propyl, isopropyl ortert-butyl, or alternatively trifluoromethyl or difluoromethyl. Morepreferable are compounds IIa in which R² is tert-butyl, difluoromethylor trifluoromethyl, and most preferred are those in which R² istert-butyl.

The compounds of the formula II can be prepared in analogy to methodswhich are well known in the art, as for example from the internationalpatent applications cited in the introductory part, WO 99/02503, WO96/0250, PCT/EP2004006139 and U.S. 60/600,042. Preferred methods areoutlined in schemes i) and ii) below:

According to this scheme, a triazole of the formula III, wherein Ar isas defined above, is reacted with a piperazinylpyrimidine compound ofthe formula IV, wherein R^(x) is SH and Y is a conventional leavinggroup such as halogen such as chlorine, bromine or iodine,alkylsulfonyloxy such as methanesulfonyloxy, arylsulfonyloxy such asphenylsulfonyloxy, or tolylsulfonyloxy (tosylate). The reaction can beperformed using the conditions as described herein or in the prior artcited in the introductory part. R^(x) may also be chlorine or bromine,while Y is SH; in this case, the reaction can be performed using thereaction conditions as described by Hester, Jackson B., Jr. and VonVoigtlander, Philip, Journal of Medicinal Chemistry (1979), 22(11).

According to this scheme, a triazole of the formula V is reacted with apiperazinylpyrimidine compound of the formula VI, wherein Y is aconventional leaving group such as halogen, alkylsulfonyloxy,arylsulfonyloxy, etc as described above.

The compounds of the formulae III and V are known in the art or can beprepared according to methods described in the literature, as forexample in Houben Weyl “Handbuch der Organischen Chemie”, 4th Ed.,Thieme Verlag, Stuttgart 1994, Volume E8/d, pages 479 et sequ.; in S.Kubota et al., Chem. Pharm. Bull 1975, 23:955, or in A. R. Katritzky, C.W. Rees (ed.), “Comprehensive Heterocyclic Chemistry”, 1st Ed. PergamonPress 1984, in particular Vol. 5, part 4a, pages 733 et seq. andliterature cited therein; or “The Chemistry of Heterocyclic Compounds”J. Wiley & Sons Inc. NY and literature cited therein. The compounds ofthe formulae III and V can be prepared according to routine methods asdescribed for example in J. A. Kiristy et al., J. Med. Chem., 21:1303 orC. B. Pollard, J. Am. Chem. Soc. 1934, 56:2199. Some of thetriazolecompounds are commercially available

Compounds of the formula III wherein Ar is Ar-1, R^(x) is chlorine orbromine can also be prepared from compounds III with R^(x) being OHaccording to the methods described by P. Viallefont et al. in Bulletinde la Société Chimique de France 1975, no. 3-4, 647-653, or by G. Mauryet al. in J. Heterocyclic Chemistry 1977, 14:1311.

A preferred route to compounds of the formula IV is shown in scheme iiibelow:

In a first step, a piperazine compound VII wherein Q is H or aprotecting group for secondary amines is reacted with a pyrimidinecompound VIII wherein Z is halogen to yield a compound of the formulaVI. This compound is then reacted with a bifunctional propane compoundY—(CH₂)₃—Y′, wherein Y and Y′ are leaving groups of differentreactivities which can be replaced by nucleophiles e.g. Y═Cl and Y′=Br.This method is known from the prior art cited in the introductory partof the application and also from WO 99/09015 and WO 03/002543. Compoundsof the formula IV wherein Y is OH may also be prepared by the methoddisclosed in WO 03/002541

A simple method of producing the compounds of formula III, wherein Ar isAr-1 and R^(x) is SH comprises the reaction of a carboxylic acid of theformula R¹—COOH with 4-methyl-3-thiosemicarbazide in the presence of1,1′-carbonyldimidazole as shown in scheme iv).

The reaction can be performed using the conditions as described hereinand in El-Deen, I. M. and Ibrahim, H. K., Phosphorus, Sulfur and Siliconand the Related Elements (2002), 177(3):733-740; Faidallah et al.,Phosphorus, Sulfur and Silicon and the Related Elements (2002),177(1):67-79; Tumkevicius, Sigitas and Vainilavicius, Povilas, Journalof Chemical Research, Synopses (2002), 5:213-215; Palaska et al., FABADJournal of Pharmaceutical Sciences (2001), 26(3):113-117; Li, Xin Zhiand Si, Zang Xing, Chinese Chemical Letters (2002), 13(2):129-132; andSuni et al., Tetrahedron (2001), 57(10):2003-2009.

The preparation of the pyrimidine compounds VIII is simply achieved byreacting tert-butylamidinium chloride with a suitable β-ketoester IX toyield a 2-tert-butyl-4-hydroxypyrimidine of the formula X which can betransformed to the halo compound VIII by reacting it with halogenatingagent such as thionyl chloride, phosphoryl chloride, phosphoryl bromide,phosphorous trichloride, phosphorous tribromide or phosphorouspentachloride (see scheme v):

β-Ketoesters IX where R² is alkyl such as propyl, isopropyl, ortert-butyl, or trifluoromethyl are commercially available and candirectly be reacted with tert-butyl-amidinium chloride, which is alsocommercially available from e.g. Maybridge Ltd.

β-Ketoesters where R² is fluoroalkyl such as difluoromethyl can besimply synthesized according to the methods described in thisapplication from the corresponding acid chlorides R²—COCl by reactionwith meldrum's acid (2,2-dimethyl-4,6-dioxo-1,3-dioxan) according to theprocess as described herein and in B. Trost et al., Journal of theAmerican Chemical Society (2002), 124(35):10396-10415; Paknikar, S. K.et al., Journal of the Indian Institute of Science (2001),81(2):175-179; and Brummell, David G. et al., Journal of MedicinalChemistry (2001), 44(1):78-93.

Compounds of the formula I (and also compounds of the formula II asdefined hereinafter) wherein n is 1 contain a sulfoxide —SO—functionality which is a center of chirality. Thus, compounds of theformulae I and II can occur in the racemic form, in the (S)-form or inthe (R)-form. The enantiomeric forms of these compounds can either beseperated via chiral column chromatography using chiral stationaryphases like CHIRALPAK AD, CHIRALPAK OD or others, with e.g.heptane-ethanol-triethylamine mixtures of varying composition as eluent,or they can be prepared by enantioselective oxidation of the sulfanylprecursors according to e.g. the following methods described inliterature or variations thereof, followed by one or morerecrystallization steps (H. Kagan et al., Bull Soc Chim Fr (1996), 133,1109-1115; F. Di Furia et al., Synthesis, 1984, 325-326; Mike S. Ansonet al., Synlett 2002, 7, 1055-1060; B. Kohl et al., WO 2004/052882; F.Rebiere et al., WO 2005/028428; F. Rebiere et al., US 20050222257; S.von Unge et al., Tetrahedron: Asymmetry 11 (2000), 3819-3825, andreferences cited therein.

If not otherwise indicated, the above-described reactions are generallycarried out in a solvent at temperatures between room temperature andthe boiling temperature of the solvent employed. Alternatively, theactivation energy which is required for the reaction can be introducedinto the reaction mixture using microwaves, something which has provedto be of value, in particular, in the case of the reactions catalyzed bytransition metals (with regard to reactions using microwaves, seeTetrahedron 2001, 57, p. 9199 ff. p. 9225 ff. and also, in a generalmanner, “Microwaves in Organic Synthesis”, André Loupy (Ed.), Wiley-VCH2002).

Examples of solvents which can be used are ethers such as diethyl ether,diisopropyl ether, methyl tert-butyl ether or tetrahydrofuran, aproticpolar solvents such as dimethylformamide, dimethyl sulfoxide,dimethoxyethane and acetonitrile, aromatic hydrocarbons such as tolueneand xylene, ketones such as acetone or methyl ethyl ketone,halohydrocarbons such as dichloromethane, trichloromethane anddichloroethane, esters such as ethyl acetate and methyl butyrate,carboxylic acids such as acetic acid or propionic acid, and alcoholssuch as methanol, ethanol, n-propanol, isopropanol and butanol.

If desired, it is possible for a base to be present in order toneutralize protons which are released in the reactions. Suitable basesinclude inorganic bases such as sodium carbonate, potassium carbonate,sodium hydrogen carbonate or potassium hydrogen carbonate, alkoxidessuch as sodium methoxide or sodium ethoxide, alkali metal hydrides suchas sodium hydride, organometallic compounds such as butyllithiumcompounds or alkylmagnesium compounds, and organic nitrogen bases suchas triethylamine or pyridine. The latter compounds can at the same timeserve as solvents.

The crude product is isolated in a customary manner, as for example byfiltering, distilling off the solvent or extracting from the reactionmixture, etc. The resulting compounds can be purified in a customarymanner, as for example by means of recrystallizing from a solvent, bymeans of chromatography or by means of converting into an acid additionsalt.

The acid addition salts are prepared in a customary manner by mixing thefree base with a corresponding acid, where appropriate in solution in anorganic solvent as for example a lower alcohol such as methanol,ethanol, n-propanol or isopropanol, an ether such as methyl tert-butylether or diisopropyl ether, a ketone such as acetone or methyl ethylketone, or an ester such as ethyl acetate. For example, the free base offormula I and suitable amounts of the corresponding acid, such as from 1to 4 moles per mol of formula I, are dissolved in a suitable solvent,preferably in a lower alcohol such as methanol, ethanol, n-propanol orisopropanol. Heating may be applied to dissolve the solids, ifnecessary. Solvents, wherein the acid addition salt of I is insoluble(anti-solvents), might be added to precipitate the salt. Suitableanti-solvents comprise C₁-C₄-alkylesters of C₁-C₄-aliphatic acids suchas ethyl acetate, aliphatic and cycloaliphatic hydrocarbons such ashexane, cyclohexane, heptane, etc., di-C₁-C₄-alkylethers such as methyltert-butyl ether or diisopropyl ether. A part or all of the anti-solventmay be added to the hot solution of the salt and the thus obtainedsolution is cooled; the remainder of the anti-solvent is then addeduntil the concentration of the salt in the mother liquor is as low asapproximately 10 mg/l or lower.

The compounds according to the invention of the formula I aresurprisingly highly selective dopamine D₃ receptor ligands. Because oftheir low affinity for other receptors such as D₁ receptors, D₄receptors, α1-adrenergic and/or α2-adrenergic receptors, muscarinergicreceptors, histamine receptors, opiate receptors and, in particular,dopamine D₂ receptors, the compounds can be expected to give rise tofewer side-effects than do the classic neuroleptics, which are D₂receptor antagonists.

The high affinity of the compounds according to the invention for D₃receptors is reflected in very low in-vitro K, values of as a rule lessthan 60 nM (nmol/l), preferably of less than 30 nM and, in particular ofless than 20 nM. The displacement of [¹²⁵I]-iodosulpride can, forexample, be used in receptor binding studies for determining bindingaffinities for D₃ receptors.

The selectivity of the compounds of the invention for the D₂ receptorrelative to the D₃ receptor, expressed as K_(i)(D₂)/K_(i)(D₃), is as arule at least 20, preferably at least 40. The displacement of[³H]SCH23390, [¹²⁵I] iodosulpride or [¹²⁵I] spiperone can be used, forexample, in carrying out receptor binding studies on D₁, D₂ and D₄receptors.

Because of their binding profile, the compounds can be used for treatingdiseases which respond to dopamine D₃ ligands, that is, they can beexpected to be effective for treating those medical disorders ordiseases in which exerting an influence on (modulating) the dopamine D₃receptors leads to an improvement in the clinical picture or to thedisease being cured. Examples of these diseases are disorders ordiseases of the central nervous system.

Disorders or diseases of the central nervous system are understood asmeaning disorders which affect the spinal cord and, in particular, thebrain. Within the meaning of the invention, the term “disorders” denotesdisturbances and/or anomalies which are as a rule regarded as beingpathological conditions or functions and which can manifest themselvesin the form of particular signs, symptoms and/or malfunctions. While thetreatment according to the invention can be directed toward individualdisorders, that is, anomalies or pathological conditions, it is alsopossible for several anomalies, which may be causatively linked to eachother, to be combined into patterns or syndromes which can be treated inaccordance with the invention.

The disorders which can be treated in accordance with the invention are,in particular, psychiatric and neurological disturbances. Thesedisturbances include, in particular, organic disturbances, includingsymptomatic disturbances such as psychoses of the acute exogenousreaction type or attendant psychoses of organic or exogenous cause asfor example in association with metabolic disturbances, infections andendocrinopathogies; endogenous psychoses such as schizophrenia andschizotype and delusional disturbances; affective disturbances such asdepressions, major depressive disorder, mania and/or manic-depressiveconditions; mixed forms of the above-described disturbances; neuroticand somatoform disturbances and also disturbances in association withstress; dissociative disturbances such as loss of consciousness,clouding of consciousness, double consciousness and personalitydisturbances; autism; disturbances in attention and waking/sleepingbehavior such as behavioral disturbances and emotional disturbanceswhose onset lies in childhood and youth as for example hyperactivity inchildren, intellectual deficits such as attention disturbances(attention deficit disorders with or without hyperactivity), memorydisturbances and cognitive disturbances such as impaired learning andmemory (impaired cognitive function), dementia, narcolepsy and sleepdisturbances such as restless legs syndrome; development disturbances;anxiety states; delirium; sexual disturbances such as impotence in men;eating disturbances such as anorexia or bulimia; addiction; bipolardisorder; and other unspecified psychiatric disturbances.

The disorders which can be treated in accordance with the invention alsoinclude Parkinson's disease and epilepsy and, in particular, theaffective disturbances connected thereto.

Also treatable are addictive diseases (substance abuse), that is,psychic disorders and behavioral disturbances which are caused by theabuse of psychotropic substances such as pharmaceuticals or narcotics,and also other addiction behaviors such as addiction to gaming and/orimpulse control disorders not elsewhere classified. Examples ofaddictive substances include opioids such as morphine, heroin andcodeine: cocaine; nicotine; alcohol; substances which interact with theGABA chloride channel complex; sedatives, hypnotics and tranquilizers asfor example benzodiazepines; LSD; cannabinoids; psychomotor stimulantssuch as 3,4-methylenedioxy-N-methylamphetamine (ecstasy); amphetamineand amphetamine-like substances such as methylphenidate; and otherstimulants including caffeine. Addictive substances which comeparticularly into consideration are opioids, cocaine, amphetamine oramphetamine-like substances, nicotine and alcohol.

With regard to the treatment of addiction diseases, particularpreference is given to those compounds according to the invention of theformula I which themselves do not possess any psychotropic effect. Thiscan also be observed in a test using rats, which, after having beenadministered compounds which can be used in accordance with theinvention, reduce their self administration of psychotropic substances,for example cocaine.

According to another aspect of the present invention, the compoundsaccording to the invention are suitable for treating disorders whosecauses can at least partially be attributed to an anomalous activity ofdopamine D₃ receptors.

According to another aspect of the present invention, the treatment isdirected, in particular, toward those disorders which can be influenced,within the sense of an expedient medicinal treatment, by the binding ofpreferably exogeneously administered binding partners (ligands) todopamine D₃ receptors.

The diseases which can be treated with the compounds according to theinvention are frequently characterized by progressive development, thatis, the above-described conditions change over the course of time; as arule, the severity increases and conditions may possibly merge into eachother or other conditions may appear in addition to those which alreadyexist.

The compounds according to the invention can be used to treat a largenumber of signs, symptoms and/or malfunctions which are connected withthe disorders of the central nervous system and, in particular, theabovementioned conditions. These signs, symptoms and/or malfunctionsinclude, for example, a disturbed relationship to reality, lack ofinsight and ability to meet customary social norms or the demands madeby life, changes in temperament, changes in individual drives, such ashunger, sleep, thirst, etc., and in mood, disturbances in the ability toobserve and combine, changes in personality, in particular emotionallability, hallucinations, ego-disturbances, distractedness, ambivalence,autism, depersonalization and false perceptions, delusional ideas,chanting speech, lack of synkinesia, short-step gait, flexed posture oftrunk and limbs, tremor, poverty of facial expression, monotonousspeech, depressions, apathy, impeded spontaneity and decisiveness,impoverished association ability, anxiety, nervous agitation,stammering, social phobia, panic disturbances, withdrawal symptoms inassociation with dependency, maniform syndromes, states of excitationand confusion, dysphoria, dyskinetic syndromes and tic disorders, suchas Huntington's chorea and Gilles-de-la-Tourette's syndrome, vertigosyndromes such as peripheral positional, rotational and oscillatoryvertigo, melancholia, hysteria, hypochondria and the like.

Within the meaning of the invention, a treatment also includes apreventive treatment (prophylaxis), in particular as relapse prophylaxisor phase prophylaxis, as well as the treatment of acute or chronicsigns, symptoms and/or malfunctions. The treatment can be orientatedsymptomatically, as for example for the suppression of symptoms. It canbe effected over a short period, be orientated over the medium term orcan be a long-term treatment, as for example within the context of amaintenance therapy.

Surprisingly, high brain levels in excess of 100 or even of 200 ng/g oreven of 500 ng/g (determined in rats as the value C_(max)) can beachieved when administering the compounds of the invention.

Therefore the compounds according to the invention are preferentiallysuitable for treating diseases of the central nervous system, inparticular for treating affective disorders; neurotic disturbances,stress disturbances and somatoform disturbances and psychoses, and, inparticular, for treating schizophrenia and depression. Because of theirhigh selectivity with regard to the D₃ receptor, the compounds Iaccording to the invention are also suitable for treating disturbancesof kidney function, in particular disturbances of kidney function whichare caused by diabetes mellitus (see WO 00/67847) and, especially,diabetic nephropathy.

In addition, compounds of the present invention may possess otherpharmacological and/or toxicological properties that render themespecially suitable for development as pharmaceuticals. As an example,compounds of formula I having a low affinity for the HERG receptor couldbe expected to have a reduced likelihood of inducing QT-prolongation(regarded as a one predictor of risk of causing cardiac arrythmia. (Fora discussion of QT-prolongation see for example A. Cavalli et al., J.Med. Chem. 2002, 45:3844-3853 and the literature cited therein; a HERGassay is commercially available from GENION Forschungsgesellschaft mbH,Hamburg, Germany).

Within the context of the treatment, the use according to the inventionof the described compounds involves a method. In this method, aneffective quantity of one or more compounds, as a rule formulated inaccordance with pharmaceutical and veterinary practice, is administeredto the individual to be treated, preferably a mammal, in particular ahuman being, productive animal or domestic animal. Whether such atreatment is indicated, and in which form it is to take place, dependson the individual case and is subject to medical assessment (diagnosis)which takes into consideration signs, symptoms and/or malfunctions whichare present, the risks of developing particular signs, symptoms and/ormalfunctions, and other factors.

As a rule, the treatment is effected by means of single or repeateddaily administration, where appropriate together, or alternating, withother active compounds or active compound-containing preparations suchthat a daily dose of preferably from about 0.01 to 1000 mg/kg, morepreferably from 0.1 to 1000 mg/kg of bodyweight in the case of oraladministration, or of from about 0.01 to 100 mg/kg, more preferably from0.1 to 100 mg/kg of bodyweight in the case of parenteral administration,is supplied to an individual to be treated.

The invention also relates to the production of pharmaceuticalcompositions for treating an individual, preferably a mammal and inparticular a human being, a farm animal or a domestic animal. Thus, thecompounds are customarily administered in the form of pharmaceuticalcompositions which comprise a pharmaceutically acceptable excipienttogether with at least one compound according to the invention and,where appropriate, other active compounds. These compositions can, forexample, be administered orally, rectally, transdermally,subcutaneously, intravenously, intramuscularly or intranasally.

Examples of suitable pharmaceutical formulations are solid medicinalforms such as powders, granules, tablets (in particular film tablets),lozenges, sachets, cachets, sugar-coated tablets, capsules such as hardgelatin capsules and soft gelatin capsules; suppositories or vaginalmedicinal forms; semisolid medicinal forms such as ointments, creams,hydrogels, pastes or plasters; and also liquid medicinal forms such assolutions, emulsions (in particular oil-in-water emulsions), suspensionssuch as lotions, injection preparations and infusion preparations, andeyedrops and eardrops. Implanted release devices can also be used foradministering inhibitors according to the invention. In addition, it isalso possible to use liposomes or microspheres.

When producing the compositions, the compounds according to theinvention are usually mixed or diluted with an excipient. Excipients canbe solid, semisolid or liquid materials which serve as vehicles,carriers or medium for the active compound.

Suitable excipients are listed in the specialist medicinal monographs.In addition, the formulations can comprise pharmaceutically acceptablecarriers or customary auxiliary substances, such as glidants; wettingagents; emulsifying and suspending agents; preservatives; antioxidants;antiirritants; chelating agents; coating auxiliaries; emulsionstabilizers; film formers; gel formers; odor masking agents; tastecorrigents; resin; hydrocolloids; solvents; solubilizers; neutralizingagents; diffusion accelerators; pigments; quaternary ammonium compounds;refatting and overfatting agents; raw materials for ointments, creams oroils; silicone derivatives; spreading auxiliaries; stabilizers;sterilants; suppository bases; tablet auxiliaries, such as binders,fillers, glidants, disintegrants or coatings; propellants; dryingagents; opacifiers; thickeners; waxes; plasticizers and white mineraloils. A formulation in this regard is based on specialist knowledge asdescribed, for example, in Fiedler, H. P., Lexikon der Hilfsstoffe fürPharmazie, Kosmetik and angrenzende Gebiete [Encyclopedia of auxiliarysubstances for pharmacy, cosmetics and related fields], 4^(th) edition,Aulendorf: ECV-Editio-Kantor-Verlag, 1996.

The following examples serve to explain the invention without limitingit.

The compounds were either characterized via proton-NMR ind₆-dimethylsulfoxid or d-chloroform on a 400 MHz or 500 MHz NMRinstrument (Bruker AVANCE), or by mass spectrometry, generally recordedvia HPLC-MS in a fast gradient on C18-material (electrospray-ionisation(ESI) mode), or melting point.

The magnetic nuclear resonance spectral properties (NMR) refer to thechemical shifts (8) expressed in parts per million (ppm). The relativearea of the shifts in the ¹H NMR spectrum corresponds to the number ofhydrogen atoms for a particular functional type in the molecule. Thenature of the shift, as regards multiplicity, is indicated as singlet(s), broad singlet (s. br.), doublet (d), broad doublet (d br.), triplet(t), broad triplet (t br.), quartet (q), quintet (quint.) and multiplet(m).

PREPARATION EXAMPLES I. Preparation of Intermediates a. Preparation of2-tert.butyl-pyrimidine-compounds IV a.12-tert-Butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-cyclobutyl-pyrimidinea.1.1: Methyl-2-cyclobutanoyl-acetate

22 g of meldrum's acid (2,2-dimethyl-1,3-dioxane-4,6-dione) (152.7 mmol)and 36.9 ml of pyridine (457.2 mmol) were dissolved in 200 ml ofdichloromethane. 18.1 g of cyclobutylcarbonic acid chloride were addedat 0 to 10° C. The reaction mixture was stirred overnight at roomtemperature, washed with 1 N HCl and extracted with di-chloromethane.The organic layer was washed with water, dried over magnesium sulfate,filtered, and then concentrated to dryness. The oily residue wasdissolved in 300 ml of methanol and heated under reflux for 2 h. Thereaction mixture was concentrated to dryness and the residue purifiedvia silica gel chromatography with ethyl acetate as eluent. Yield: 21.2g

MS (ESI) m/z: 157.1 [M+H]⁺

¹H-NMR (CDCl₃): δ [ppm] 3.7 (s, 3H), 3.4 (s, 2H), 3.3-3.4 (m, 1H),2.2-2.4 (m, 2H), 2.1-2.25 (m, 2H), 1.9-2.1 (m, 1H), 1.8-1.9 (m, 1H).

a.1.2: 2-tert-Butyl-4-hydroxy-6-cyclobutyl-pyrimidine

9.2 g of tert-butyl amidinium chloride (67.3 mmol, Maybridge) and 12.6 gof methyl-2-cyclobutanoyl acetate (80.7 mmol) were dissolved/suspendedin 100 ml of methanol. 14.5 g of sodium methanolate (268.4 mmol) wereadded in portions to the solution at 10° C. The suspension was thenstirred at room temperature overnight. The reaction mixture wasconcentrated to roughly half the volume and filtered. The filtrate wasextracted with water and dichloromethane. The organic phase was driedover magnesium sulfate, filtered, and then concentrated to dryness. Theresidue was stirred with acetone and the precipitate was collected byfiltration. Yield: 11.9 g (85.7%).

MS (ESI) m/z: 207.2 [M+H]⁺

a.1.3: 2-tert-Butyl-4-chloro-6-cyclobutyl-pyrimidine

9.9 g of 2-tert-butyl-4-hydroxy-6-cyclobutyl-pyrimidine (48 mmol) weredissolved in 80 ml of toluene and 1 ml of dimethylformamide. 10.7 ml ofPOCl₃ (114.8 mmol) were added dropwise at 10° C. Stirring was continuedfor 3 h at room temperature. The reaction mixture was poured into water,and the aqueous layer extracted with dichloromethane. The organic layerwas dried over magnesium sulfate, filtered, and then concentrated todryness to give 10.8 g of a yellowish oil (quant.).

a.1.4: 2-tert-Butyl-4-(piperazin-1-yl)-6-cyclobutyl-pyrimidine

24.8 g of piperazine (287.9 mmol) were dissolved in 350 ml of ethanoland heated to reflux. 24.9 g of2-tert-butyl-4-chloro-6-cyclobutyl-pyrimidine (48.06 mmol), dissolved in50 ml of ethanol, were added dropwise to the solution. The solution wasrefluxed for further 3 h, cooled to room temperature and then extractedwith water and ethyl acetate. The organic layer was washed with 5%citric acid (aq.), and the aqueous layer was adjusted to alkaline pHwith 2 N NaOH. The alkaline aqueous layer was reextracted with ethylacetate, and the organic phase was dried over magnesium sulfate,filtered and concentrated to dryness to yield 8.6 g (65.2%) of the titlecompound.

MS (ESI) m/z: 275.2 [M+H]⁺

¹H-NMR (CDCl₃): δ [ppm] 6.1 (s, 1H), 3.6 (m, 4H), 3.4 (m, 1H), 2.9 (m,4H), 2.3 (m, 4H), 1.8-2.1 (m, 3H), 1.3 (s, 9H) a.1.5:2-tert-Butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-cyclobutyl-pyrimidine

3.5 g of 2-tert-butyl-4-(piperazin-1-yl)-6-cyclobutyl-pyrimidine (12.75mmol), 2.3 g of 1-bromo-3-chloro-propane (14.6 mmol) and 2.8 ml oftriethylamine (20.1 mmol) were dissolved in 70 ml of dimethylformamide.The mixture was stirred at room temperature overnight and for further 3h at 40° C. The reaction mixture was then extracted with water and ethylacetate. The organic layer was dried over magnesium sulfate, filtered,and concentrated to dryness. The crude product was then purified bysilica gel chromatography (dichloromethane as eluent) to yield 3.0 g(67%) of the title compound.

a.22-tert-Butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-(1-methylcyclopropyl)-pyrimidinewas obtained by analogy to the method outlined in a.1: MS (ESI) m/z:351.2 [M+H]⁺ a.3.2-tert-Butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-n-propylpyrimidinewas obtained by analogy to the method outlined in a.1: MS (ESI) m/z:339.2 [M+H]⁺ a.4.2-tert-Butyl-6-tert.-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]pyrimidinewas obtained by analogy to the method outlined in a.1: MS (ESI) m/z:353.3 [M+H]⁺ a.5.2-tert-Butyl-6-trifluoromethyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]pyrimidinewas obtained by analogy to the method outlined in a.1. b. Preparation of3-mercapto-4-methyl-triazoles III b.14-Methyl-5-methyl-4H-[1,2,4]-triazole-3-thiol

-   -   62.4 g of N,N′-carbonyldiimidazol (0.385 mol) were added in        portions within 10 min. to a mixture of 22 g of acetic acid        (0.366 mol) and 300 ml of dimethylformamide. The temperature        rose from 22° C. to about 26° C. After the addition was        completed, stirring was continued for 30 min. Then 38.5 g of        4-methyl-3-thiosemicarbazid (0.366 mol) and 100 ml of pyridine        were added. The reaction mixture was heated to 100° C. and        stirred for 4 h at this temperature. Stirring was continued for        14 h at room temperature. The solvent was evaporated under        reduced pressure. The residue was treated with 200 ml of        isopropanol and 150 ml of ethyl acetate, and re-dissolved at        80° C. Crystallization of the product started during cooling to        room temperature. 300 ml of isopropanol were added and the        obtained suspension was stirred for 1 h at room temperature. The        precipitate was collected by filtration, washed twice with 75 ml        of isopropanol each and dried under vacuum at 40° C. to yield        20.4 g of the title compound.

MS (ESI) m/z: 130.1 [M+H]⁺

¹H-NMR (DMSO): δ [ppm] 13.4 (s, broad, 1H), 3.4 (s, 3H), 2.3 (s, 3H)

b.2. 4-Methyl-5-methoxymethyl-4H-[1,2,4]triazole-3-thiol

-   -   5 g of methoxy-acetic acid (55.5 mmol) were dissolved in 70 ml        of dimethylformamide. 11.73 g of 1,1′-carbonyldiimidazol (72.3        mmol) were added in portions within 10 min. After 30 min. at        room temperature 23 ml of pyridine were added. Then 5.84 g of        4-methyl-3-thiosemicarbazide (55.5 mmol) were added and the        obtained solution was stirred at room temperature overnight, and        for an additional 3 h at 100° C. The solvent was evaporated, the        residue dissolved in 70 ml of saturated aqueous sodium chloride        solution and 30 ml of water. The aqueous layer was extracted six        times with 100 ml of ethyl acetate each, and the combined        organic layers were dried over magnesium sulfate, filtered, and        the solvent was evaporated to dryness to yield 17 g of the crude        title compound, which was further purified by silica gel        chromatography with ethyl acetate, thereby obtaining 7.1 g of        the purified title compound.

MS (ESI) m/z: 160.1 [M+H]⁺

b.3 5-Ethyl-4-methyl-4H-[1,2,4]triazole-3-thiol was obtained by analogyto method b.2: MS (ESI) m/z: 144.1 [M+H]⁺ b.44-Methyl-5-(4-fluorophenyl)-4H-[1,2,4]triazole-3-thiol was purchasedfrom Chembridge Corporation b.55-Cyclobutyl-4-methyl-4H-[1,2,4]triazole-3-thiol was obtained by analogyto method b.2: MS (ESI) m/z: 170.1 [M+H]⁺ b.64-Methyl-4H-[1,2,4]triazole-3-thiol was purchased from Aldrich b.74-Methyl-5-phenyl-4H-[1,2,4]triazole-3-thiol was purchased fromChembridge Corporation b.85-Cyclopropyl-4-methyl-4H-[1,2,4]triazole-3-thiol was obtained byanalogy to method b.2: MS (ESI) m/z: 156.1 [M+H]⁺ b.94-Methyl-5-trifluoromethyl-4H-[1,2,4]triazole-3-thiol was purchased fromAcros b.10 4-Methyl-5-(1-methylpyrrol-2-yl)-4H-[1,2,4]triazole-3-thiolwas obtained by analogy to method b.2 c: Preparation of compounds II c.12-tert-Butyl-4-{(4-[3-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1-yl}-6-cyclobutylpyrimidine

-   -   0.8 g of        2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-cyclobutyl-pyrimidine        (2.28 mmol), 0.29 g of 4-methyl-3-mercapto-1,2,4-triazole (2.52        mmol), 0.15 g of lithium hydroxide and a tip of a spatula of        potassium iodide were dissolved in 20 ml of dimethylformamide.        The mixture was stirred for 14 h at room temperature and then        extracted with water and ethyl acetate. The organic layer was        dried over magnesium sulfate, filtered, and evaporated to        dryness. The residue was then purified by column chromatography        on silica gel (dichloromethane-methanol (2-10%)) to yield an        oily residue that was precipitated with acetonitrile thereby        yielding 0.46 g of the title compound (47%).

MS (ESI) m/z: 430.5 [M+H]⁺

¹H-NMR (DMSO): δ [ppm] 8.1 (s, 1H), 6.1 (s, 1H), 3.15 (m, 4H), 3.1 (s,3H), 3.4 (m, 1H), 3.3 (m, 2H), 2.45 (m, 6H), 2.25 (m, 4H), 2.0 (m, 3H),1.9 (m, 1H), 1.3 (s, 9H).

c.22-tert-Butyl-4-{4-[3-(4-methyl-5-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1-yl}-6-tert-butyl-pyrimidinehydrochloride

-   -   1 g of        2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-tert-butyl-pyrimidine        (2.83 mmol), 0.4 g of        4-methyl-5-methyl-4H-[1,2,4]-triazole-3-thiol (3.09 mmol), 0.2 g        of lithium-hydroxide (8.35 mmol) and a spatula tip of potassium        iodide werde stirred in 20 ml of dimethylformamide for 2 h at        80° C. After addition of water and ethyl acetate, the organic        phase was separated and dried over magnesium sulfate. After        filtration and evaporation of the solvent, the crude product was        purified by column chromatography on silica gel using        dichloromethane-methanol (1-6%). Fractions containing the        product were combined and the solvent was evaporated. The        residue was dissolved in isopropanol, and a solution of HCl in        isopropanol was added. On addition of diisopropylethylether, the        product formed an oily mass. The solvent was decanted and the        remaining oil evaporated to dryness to yield 0.6 g (41%) of the        title compound as a white solid.

MS (ESI) m/z: 446.3 [M+H]⁺

¹H-NMR (DMSO): δ [ppm] 12.0 (s, 1H, broad), 6.8 (s, 1H, broad), 4.7 (m,2H, broad), 3.4-3.7 (m, 4H, very broad), 3.6 (s, 3H), 3.4 (m, 2H), 3.25(m, 2H), 3.0-3.4 (m, 2H, very broad), 2.6 (s, 3H), 2.2 (m, 2H), 1.4 (s,18H, broad)

c.32-tert-Butyl-4-{4-[3-(4-methyl-5-cyclopentyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1-yl}-6-trifluoromethyl-pyrimidinetrifluoroacetate

-   -   1 g of        2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-trifluoromethyl-pyrimidine        (2.74 mmol) and 0.55 g of        4-methyl-5-cyclopentyl-4H-[1,2,4]triazole-3-thiol (3.0 mmol)        were dissolved in 10 ml of n-butanol. After addition of 0.197 g        of lithium hydroxide (8.22 mmol) and 0.205 g of sodium iodide        (1.37 mmol), the reaction mixture was heated to 79° C. for 3 h.        After cooling, the solution was filtered, and the filtrate        evaporated to dryness. The residue was partitioned between 30 ml        of ethyl acetate, 20 ml of water and 20 ml of an aqueous        saturated solution of sodium chloride. The aqueous layer was        re-extracted twice with 30 ml of ethyl acetate each. The        combined organic layers were dried over magnesium sulfate,        filtered, and the solvent was evaporated. The residue was        purified by preparative HPLC on a C18-Symmetry column (Waters).        Fractions containing the product were combined and lyophilised        to yield 0.25 g of the title compound.

MS (ESI) m/z: 512.3 [M+H]⁺

¹H-NMR (DMSO): δ [ppm] 7.05 (s, 1H), 3.75 (m, broad, 4H), 3.5 (s, 3H),3.2 (m, 1H), 3.15 (m, 2H), 2.45 (m, 6H), 2.05 (m, 2H), 1.85 (m, 4H),1.75 (m, 2H), 1.65 (m, 2H), 1.3 (s, 9H)

c.42-tert-Butyl-4-{4-[3-(4-methyl-5-methoxymethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1-yl}-6-difluoromethyl-pyrimidinehydrochloride

-   -   0.6 g of 4-methyl-5-methoxymethyl-4H-[1,2,4]triazole-3-thiol        (3.77 mmol), 0.09 g of lithium hydroxide (3.77 mmol) and 0.28 g        sodium iodide (1.88 mmol) were dissolved in 20 ml of        dimethylformamide. Within 2 h, a solution of 1.31 of g        2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-difluoromethyl-pyrimidine        (3.77 mmol) in 5 ml of dimethylformamide was added at 70° C.        Stirring was continued for 1 h at 80° C. After cooling, the        solvent was evaporated and the remaining oily residue was        partitioned between 30 ml of ethyl acetate, 15 ml of water and        15 ml of a saturated aqueous solution of sodium chloride. The        aqueous layer was re-extracted twice with 20 ml ethyl acetate        each and the organic layers were combined, dried over magnesium        sulfate, filtered, and the solvent was evaporated. The residue        was purified by column chromatography on silica gel employing in        succession dichloromethane-ethyl acetate 1:1, ethyl acetate, and        ethyl acetate-methanol 5:1. Fractions containing the product        were combined, the solvents was evaporated and the residue was        re-dissolved in 15 ml ethyl acetate. A 4 N solution of HCl in        diethyl ether was added to precipitate the hydrochloride salt.        The solution was decanted and the residue dried.    -   Yield: 0.55 g.

MS (ESI) m/z: 470.2 [M+H]⁺

¹H-NMR (DMSO): δ [ppm] 11.95 (s, 1H, broad), 9.8 (s, 3H, broad), 7.0 (s,1H), 6.8 (t, 1H, CHF2), 4.7 (s, 2H), 4.6 (m, 2H, broad), 3.45-3.7 (m,4H, broad), 3.6 (s, 3H), 3.4 (m, 2H), 3.35 (s, 3H), 3.2 (m, 2H),2.95-3.2 (m, 2H, broad), 2.2 (m, 2H), 1.3 (s, 9H), 1.2 (m, 1H)

c.52-tert-Butyl-4-{4-[3-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1-yl}-6-tert-butyl-pyrimidinehydrochloride

-   -   1 g of        2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-tert-butyl-pyrimidine        (2.83 mmol), 0.35 g of 4-methyl-4H-[1,2,4]triazole-3-thiol (3.04        mmol), 0.2 g of lithium-hydroxide (8.35 mmol) and a spatula tip        of potassium iodide were stirred for 72 h in 20 ml of        dimethylformamide. Water and ethyl acetate were added and the        organic layer was separated, dried over magnesium sulfate,        filtered and the solvent was evaporated. The residue was        subjected to a column chromatography on silica gel using        dichloromethane-methanol (2-10%). Fractions containing the        product were cornbined, the solvent was evaporated and the        residue re-dissolved in isopropanol. The solution was treated        with HCl/isopropanol. Diisopropylethylether was added whereby an        oily precipitate formed. The solvent was decanted and the        remaining oil evaporated to dryness to yield 1.1 g (77%) of the        title compound as a white solid.

MS (ESI) m/z: 432.2 [M+H]⁺

¹H-NMR (DMSO): δ [ppm] 12.5 (s, 1H, broad), 12.1 (s, 1H, broad), 9.65(s, 1H), 6.85 (s, 1H), 5.0 (m, broad, 1H), 4.7 (m, broad, 1H), 3.75 (m,1H), 3.7 (s, 3H), 3.65 (m, broad, 3H), 3.45 (m, 2H), 3.25 (m, 2H), 3.2(m, 2H), 2.2 (m, 2H), 1.45 (m, 18H).

c.62-tert-Butyl-4-{4-[3-(4-methyl-5-trifluoromethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1-yl}-6-difluoromethyl-pyrimidinehydrochloride

-   -   0.5 g of 4-methyl-5-trifluoromethyl-4H-[1,2,4]triazole-3-thiol        (2.73 mmol), 0.07 g of lithium hydroxide (2.73 mmol) and 0.2 g        of sodium iodide (1.36 mmol) were dissolved in 20 ml of        dimethylformamide. Within 1 h, a solution of 0.95 g of        2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-difluoromethyl-pyrimidine        (2.73 mmol) in 4 ml of dimethylformamide was added at 70° C.        Stirring was continued for 3 h at 70° C. After cooling, the        solvent was evaporated and the remaining oily residue        partitioned between 30 ml of ethyl acetate, 15 ml of water plus        10 ml of a saturated aqueous solution of sodium chloride. The        aqueous layer was re-extracted twice with 15 ml of ethyl acetate        each, and the combined organic layers were dried over magnesium        sulfate, filtered, and the solvent was evaporated. The crude        product was purified by column chromatography on silica gel        using ethyl acetate. Fractions containing the product were        combined, the solvent was evaporated and the residue was        re-dissolved in 20 ml of ethyl acetate. A 1N solution of HCl in        diethyl ether was added to precipitate the title compound as the        hydrochloride salt. The solution was cautiously evaporated to        dryness to yield 0.64 g of the title compound as a white        crystalline material.

MS (ESI) m/z: 494.2 [M+H]⁺

¹H-NMR (DMSO): δ [ppm] 11.8 (s, 1H, broad), 7.1 (s, 1H), 6.7-7.0 (t, 1H,CHF₂), 3.7 (s, 2H), 3.6 (m, 4H), 3.4 (m, 2H), 3.25 (m, 2H), 3.1 (m, 2H),2.2 (m, 2H), 1.3 (s, 9H),

c. 72-tert-Butyl-4-{4-[3-(4-methyl-5-tert-butyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1-yl}-6-difluoromethyl-pyrimidinehydrochloride

-   -   1.0 g of        2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-difluoromethyl-pyrimidine        (2.88 mmol), 0.5 g of        4-methyl-5-tert-butyl-4H-[1,2,4]triazole-3-thiol (2.92 mmol),        0.17 g lithium-hydroxide (7.1 mmol) and a spatula tip of        potassium iodide were stirred in 30 ml of dimethylformamide for        14 h at room temperature. After addition of water and ethyl        acetate, the organic layer was separated and dried over        magnesium sulfate. After filtration and evaporation of the        solvent, the crude product was purified by column chromatography        on silica gel using dichloromethane-methanol (2%). Fractions        containing the product were combined and the solvents were        evaporated. The residue was dissolved in isopropanol and a        solution of HCl in isopropanol was added. The thus formed        precipitate was collected and dried thoroughly to yield 0.6 g        (37.5%) of the title compound.

MS (ESI) m/z: 482.4 [M+H]⁺

¹H-NMR (DMSO): δ [ppm]7.0 (s, 1H), 6.8 (t, 1H, CHF2), 4.6 (m, broad,2H), 3.8 (s, 3H), 3.55 (m, broad, 4H), 3.45 (m, 2H), 3.2 (m, 2H), 3.1(m, 2H), 2.2 (m, 2H), 1.5 (s, 9H), 1.3 (s, 9H).

The compounds II of examples c.8 to c.29 were prepared in a similarmanner as described in the examples c.1 to c.7:

c.82-tert-Butyl-4-{4-[3-(4-methyl-5-trifluoromethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1-yl}-6-tert-butyl-pyrimidinehydrochloride

-   -   Reaction of 0.5 g of        2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-tert-butyl-pyrimidine        (1.42 mmol) and 0.28 g of        4-methyl-5-trifluoromethyl-4H-[1,2,4]triazole-3-thiol (1.53        mmol) yielded 0.35 g (43%) of the title compound as a white        solid.

MS (ESI) m/z: 500.3 [M+H]⁺

¹H-NMR (DMSO): δ [ppm] 12.5 (s, 1H, broad), 12.1 (s, 1H, broad), 6.9 (s,1H), 4.7 (m, 2H, broad), 3.85 (m, broad, 2H), 3.7 (s, 3H), 3.65 (m, 2H),3.4 (m, 2H), 3.25 (m, 2H), 3.2 (m, 2H), 2.2 (m, 2H), 1.45 (m, 18H),

c.92-tert-Butyl-4-{4-[3-(4-methyl-5-cyclopropyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1-yl}-6-tert-butyl-pyrimidinehydrochloride

-   -   Reaction of 0.5 g of        2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-tert-butyl-pyrimidine        (1.42 mmol) with 0.22 g of        4-methyl-5-cyclopropyl-4H-[1,2,4]triazole-3-thiol (1.42 mmol)        yielded 0.32 g of the title compound.

MS (ESI) m/z: 472.4 [M+H]⁺

c.102-tert-Butyl-4-{4-[3-(4-methyl-5-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1-yl}-6-propyl-pyrimidinehydrochloride

-   -   Reaction of 1 g of        2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-propyl-pyrimidine        (2.95 mmol) with 0.42 g of        4-methyl-5-methyl-4H-[1,2,4]triazole-3-thiol (3.25 mmol) yielded        0.5 g (33.6%) of title compound as a solid.

MS (ESI) m/z: 432.2 [M+H]⁺

¹H-NMR (DMSO): δ [ppm] 14.4 (s, 1H, broad), 12.1 (s, 1H, broad), 7.15(s, 1H), 5.0 (m, broad, 1H), 4.5 (s, broad, 1H), 3.75 (m, 1H), 3.7 (m,broad, 3H), 3.65 (s, 3H), 3.4 (m, 2H), 3.3 (m, 2H), 3.25 (m, broad, 2H),2.95 (m, 2H), 2.65 (s, 3H), 2.2 (m, 2H), 1.7 (m, 2H), 1.4 (s, 9H), 0.9(m, 3H)

c.112-tert-Butyl-4-{4-[3-(4-methyl-5-ethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1-yl}-6-propyl-pyrimidinehydrochloride

-   -   Reaction of 0.3 g of 4-methyl-5-ethyl-4H-[1,2,4]triazole-3-thiol        (2.09 mmol) with 0.71 g of        2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-propyl-pyrimidine        (2.09 mmol) yielded 0.63 g of the title compound.

MS (ESI) m/z: 446.3 [M+H]⁺

¹H-NMR (DMSO): δ [ppm] 14.25 (s, 1H, broad), 12.1 (s, 1H, broad), 7.15(s, 1H), 5.0 (m, 1H, broad), 4.4 (m, 1H, broad), 3.0-4.0 (m, broad, 6H),3.6 (s, 3H), 3.35 (m, 2H), 3.25 (m, 2H), 2.9 (m, 4H), 2.15 (m, 2H), 1.7(m, 2H), 1.45 (s, 9H), 1.3 (m, 3H), 0.95 (m, 3H)

c.122-tert-Butyl-4-{4-[3-(4-methyl-5-methoxymethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1-yl}-6-propyl-pyrimidinehydrochloride

-   -   0.35 g of 4-methyl-5-methoxymethyl-4H-[1,2,4]triazole-3-thiol        (2.19 mmol) were reacted with 0.75 g of        2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-propyl-pyrimidine        (2.19 mmol) to yield 0.79 g of the title compound.

MS (ESI) m/z: 462.3 [M+H]⁺

¹H-NMR (DMSO): δ [ppm] 14.4 (s, 1H, broad), 12.1 (s, 1H, broad), 7.9 (s,broad, 2H), 7.2 (s, 1H), 5.0 (m, 1H, broad), 4.7 (s, 3H), 4.5 (m, 1H,broad), 3.85 (m, 1H), 3.9-3.5 (m, 3H), 3.65 (s, 3H), 3.1-3.45 (m, 6H),2.95 (m, 2H), 2.2 (m, 2H), 1.7 (m, 2H), 1.45 (s, 9H), 0.95 (m, 3H)

c.132-tert-Butyl-4-{4-[3-(4-methyl-5-trifluoromethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1-yl}-6-trifluoromethyl-pyrimidinehydrochloride

-   -   1 g of        2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-trifluoromethyl-pyrimidine        (2.74 mmol) were reacted with 0.55 g of        4-methyl-5-trifluoromethyl-4H-[1,2,4]triazole-3-thiol (3 mmol)        to yield 0.7 g (43.7%) of the title compound as a white solid.

MS (ESI) m/z: 512.2 [M+H]⁺

¹H-NMR (DMSO): δ [ppm] 11.7 (s, 1H, broad), 7.25 (s, 1H), 4.55 (m,broad, 1H), 3.7 (s, 3H), 3.6 (m, 5H), 3.4 (m, 2H), 3.25 (m, 2H), 3.1 (m,2H), 2.25 (m, 2H), 1.3 (s, 9H)

c.142-tert-Butyl-4-{4-[3-(4-methyl-5-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1-yl}-6-trifluoromethyl-pyrimidinehydrochloride

-   -   3 g of 4-methyl-5-methyl-4H-[1,2,4]triazole-3-thiol (23.22 mmol)        were reacted with 8.47 g of        2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-trifluoromethyl-pyrimidine        (23.22 mmol) to yield 8.7 g of the title compound.

MS (ESI) m/z: 458.4 [M+H]⁺

¹H-NMR (DMSO): δ [ppm] 11.9 (s, 1H, broad), 7.2 (s, 1H), 4.7 (m, 2H),3.5-3.8 (m, 7H), 3.4 (m, 2H), 3.2 (m, 2H), 3.1 (m, 2H), 2.6 (s, 3H), 2.2(m, 2H), 1.3 (s, 9H)

c.152-tert-Butyl-4-{4-[3-(4-methyl-5-ethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1-yl}-6-trifluoromethyl-pyrimidinehydrochloride

-   -   1.5 g of 4-methyl-5-ethyl-4H-[1,2,4]triazole-3-thiol (10.75        mmol) were reacted with 3.92 g of        2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-trifluoromethyl-pyrimidine        (10.75 mmol) to yield 3.0 g of the title compound.

MS (ESI) m/z: 472.2 [M+H]⁺

¹H-NMR (DMSO): δ [ppm] 11.9 (s, 1H, broad), 7.25 (s, 1H), 4.4-5.0 (m,2H, broad), 3.25-3.75 (m, broad, 4H), 3.6 (s, 3H), 3.4 (m, 2H), 3.2 (m,2H), 3.1 (m, 2H), 2.95 (m, 2H), 2.2 (m, 2H), 1.2-1.4 (m, 12H),

c.162-tert-Butyl-4-{4-[3-(4-methyl-5-methoxymethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1-yl}-6-trifluoromethyl-pyrimidinehydrochloride

-   -   1.5 g of 4-methyl-5-methoxymethyl-4H-[1,2,4]triazole-3-thiol        (9.42 mmol) were reacted with 3.44 g        2-tert-Butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-trifluoromethyl-pyrimidine        (9.42 mmol) to yield 3.1 g of the title compound.

MS (ESI) m/z: 488.3 [M+H]⁺

¹H-NMR (DMSO): δ [ppm] 14.4 (s, 1H, broad), 12.1 (s, 1H, broad), 7.9 (s,broad, 2H), 7.2 (s, 1H), 5.0 (m, 1H, broad), 4.7 (s, 3H), 4.5 (m, 1H,broad), 3.85 (m, 1H), 3.9-3.5 (m, 3H), 3.65 (s, 3H), 3.1-3.45 (m, 6H),2.95 (m, 2H), 2.2 (m, 2H), 1.7 (m, 2H), 1.45 (s, 9H), 0.95 (m, 3H)

c.172-tert-Butyl-4-{4-[3-(4-methyl-5-cyclopropyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1-yl}-6-trifluoromethyl-pyrimidinehydrochloride

-   -   0.53 g of 4-methyl-5-methyl-4H-[1,2,4]triazole-3-thiol (3 mmol)        were reacted with 1.09 g of        2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-trifluoromethyl-pyrimidine        to yield 0.77 g of the title compound as a solid.    -   Melting point: 182-184° C.

¹H-NMR (CDCl₃): δ [ppm] 6.6 (s, 1H), 3.75 (m, 4H, broad), 3.6 (s, 3H),3.2 (m, 2H), 2.6 (m, broad, 6H), 2.0 (m, broad, 2H), 1.75 (m, 1H), 1.3(s, 9H), 1.1 (m, 2H), 1.05 (m, 2H)

c.182-tert-Butyl-4-{4-[3-(4-methyl-5-cyclobutyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1-yl}-6-trifluoromethyl-pyrimidineacetate

-   -   1 g of        2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-trifluoromethyl-pyrimidine        (2.74 mmol) were reacted with 0.46 g of        4-methyl-5-cyclobutyl-4H-[1,2,4]triazole-3-thiol (2.74 mmol) to        yield after lyophilisation 0.12 g of the product.

MS (ESI) m/z: 498.2 [M+H]⁺

¹H-NMR (DMSO): δ [ppm] 7.05 (s, 1H), 3.75 (m, broad, 4H), 3.4 (s, 3H),3.1 (m, 2H), 3.15 (m, 2H), 2.45 (m, 6H), 2.35 (m, 4H), 2.05 (m, 1H),1.85 (m, 2H), 1.75 (m, 2H), 1.3 (s, 9H).

c.192-tert-Butyl-4-{-[3-(4-methyl-5-cyclopropyl-4H-[1,2,4]-triazol-3-ylsulfanyl)-propyl]-piperazin-1-yl}-6-ethyl-pyrimidinehydrochloride

-   -   1 g of 4-methyl-5-cyclopropyl-4H-[1,2,4]triazole-3-thiol (6.44        mmol) were reacted with 2.09 g of        2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-ethyl-pyrimidine        (6.44 mmol) to yield 1.2 g of the title compound.

MS (ESI) m/z: 444.4 [M+H]⁺

-   -   1H-NMR (DMSO):): δ [ppm] 14.35 (s, 1H, broad), 12.1 (s, 1H,        broad) 7.15 (s, 1H), 5.0 (m, 1H, very broad), 4.5 (m, 1H, very        broad), 3.05-4.0 (several m, very broad, 6H), 3.75 (s, 3H), 3.4        (m, 2H), 3.25 (m, 2H), 3.0 (m, 2H), 2.3 (m, 1H), 2.2 (m, 2H),        1.45 (s, 9H), 1.2-1.35 (m, 7H)

c.202-tert-Butyl-4-{4-[3-(4-methyl-5-cyclobutyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1-yl}-6-difluoromethyl-pyrimidinehydrochloride

-   -   0.488 g of 4-methyl-5-cyclobutyl-4H-[1,2,4]triazole-3-thiol        (2.88 mmol) were reacted with 1 g of        2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-difluoromethyl-pyrimidine        (2.88 mmol) to yield 0.44 g of the product as a white solid        after drying.

MS (ESI) m/z: 480.4 [M+H]⁺

¹H-NMR (DMSO): δ [ppm] 11.8 (s, broad, 1H), 7.05 (s, 1H), 6.75 (t, 1H,CHF2), 4.6 (m, broad, 2H), 3.85 (m, 1H), 3.55 (m, broad, 4H), 3.5 (s,3H), 3.4 (m, 2H), 3.2 (m, 2H), 3.1 (m, 2H), 2.35-2.55 (m, 4H), 2.2 (m,2H), 2.1 (m, 1H), 1.9 (m, 1H), 1.3 (s, 9H)

c.212-tert-Butyl-4-{4-[3-(4-methyl-5-cyclopropyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1-yl}-6-difluoromethyl-pyrimidinehydrochloride

-   -   0.67 g of 4-methyl-5-cyclopropyl-4H-[1,2,4]triazole-3-thiol        (4.32 mmol) were reacted with 1.5 g of        2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-difluoromethyl-pyrimidine        (4.32 mmol) to yield 0.45 g of the title compound.

MS (ESI) m/z: 466.4 [M+H]⁺,

¹H-NMR (DMSO): δ [ppm] 11.95 (s, 1H, broad), 9.8 (s, 3H, broad), 7.0 (s,1H), 6.8 (t, 1H, CHF2), 4.7 (s, 2H), 4.6 (m, 2H, broad), 3.45-3.7 (m,3H, broad), 3.6 (s, 3H), 3.4 (m, 2H), 3.35 (s, 3H), 3.2 (m, 2H),2.95-3.2 (m, 2H, broad), 2.2 (m, 2H), 2.0 (s, 1H), 1.3 (s, 9H), 1.2 (m,1H)

c.222-tert-Butyl-4-{4-[3-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1-yl}-6-propyl-pyrimidinefumarate

-   -   Reaction of 1 g of        2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-propyl-pyrimidine        (2.95 mmol) with 0.37 g of 4-methyl-4H-[1,2,4]triazole-3-thiol        (3.21 mmol) yielded 0.33 g (21%) of the title compound as a        solid.

MS (ESI) m/z: 418.1 [M+H]⁺

¹H-NMR (DMSO): δ [ppm] 8.6 (s, 1H), 6.65 (s, 2H, fumarate), 6.45 (s,1H), 3.65 (m, 4H), 3.6 (s, 3H), 3.15 (m, 2H), 2.6 (m, 6H), 2.45 (m, 2H),1.9 (m, 2H), 1.65 (m, 2H), 1.25 (s, 9H), 0.9 (m, 3H)

c.232-tert-Butyl-4-{4-[3-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1-yl}-6-trifluoromethyl-pyrimidinehydrochloride

-   -   1 g of 4-methyl-4H-[1,2,4]triazole-3-thiol (8.7 mmol) were        reacted with 3.2 g of        2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-trifluoromethyl-pyrimidine        (8.7 mmol to yield 2.1 g of the title compound as a solid.    -   Melting point: 92-95° C.

MS (ESI) m/z: 444 [M+H]⁺

¹H-NMR (CDCl₃): δ [ppm] 8.15 (s, 1H), 6.6 (s, 1H), 3.75 (m, broad, 4),3.6 (s, 3H), 2.55 (m, 6H), 2.0 (m, 2H), 1.35 (s, 9H)

c.242-tert-Butyl-4-{4-[3-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1-yl}-6-difluoromethyl-pyrimidinehydrochloride

-   -   0.33 g of 4-methyl-4H-[1,2,4]triazole-3-thiol (2.88 mmol) were        reacted with 1 g of        2-tert-Butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-difluoromethyl-pyrimidine        (2.88 mmol) to yield 0.444 g of the product as a white solid.

MS (ESI) m/z: 426.4 [M+H]⁺

¹H-NMR (DMSO): δ [ppm] 11.9 (s, broad, 1H), 9.6 (s, 1H), 7.65 (s, broad,4H), 7.05 (s, 1H), 6.8 (t, 1H, CHF2), 4.65 (m, broad, 2H), 3.75 (s, 3H),3.6 (m, broad, 4H), 3.4 (m, 2H), 3.25 (m, 2H), 3.1 (m, 2H), 2.2 (m, 2H),1.3 (s, 9H).

c.252-tert-Butyl-4-{4-[3-(4-methyl-5-trifluoromethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1-yl}-6-propyl-pyrimidinehydrochloride

-   -   Reaction of 1 g of        2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-propyl-pyrimidine        (2.95 mmol) with 0.6 g        4-Methyl-5-trifluoromethyl-4H-[1,2,4]triazole-3-thiol (3.28        mmol), yielded 0.3 g (18%) of the title compound as crystalline        hydrochloride salt.

MS (ESI) m/z: 486.2 [M+H]⁺

¹H-NMR (DMSO): δ [ppm] 14.3 (s, 1H, broad), 12.1 (s, 1H, broad), 7.15(s, 1H), 5.0 (m, 1H), 4.5 (m, 1H), 3.85 (m, 1H), 3.5-3.8 (m, 3H), 3.7(s, 3H), 3.4 (m, 2H), 3.2 (m, 4H), 2.9 (m, 2H), 2.2 (m, 2H), 1.7 (m,2H), 1.45 (s, 9H), 0.95 (m, 3H)

c.262-tert-Butyl-4-{4-[3-(4-methyl-5-isopropyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1-yl}-6-trifluoromethyl-pyrimidinehydrochloride

-   -   0.5 g of 4-methyl-5-isopropyl-4H-[1,2,4]triazole-3-thiol (3.18        mmol) were reacted with 1.16 g of        2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-trifluoromethyl-pyrimidine        (3.18 mmol) to yield 1.1 g of the title compound.

MS (ESI) m/z: 486.2 [M+H]⁺

¹H-NMR (DMSO): δ [ppm] 11.6 (s, 1H, broad), 7.2 (s, 1H), 4.1 (m, 2H,broad), 3.7 (s, 3H), 3.6 (m, 4H, broad), 3.35-3.45 (m, 3H), 3.25 (m,2H), 3.1 (m, 2H), 2.2 (m, 2H), 1.4 (d, 6H), 1.3 (s, 9H)

c.272-tert-Butyl-4-{4-[3-(4-methyl-5-tert-butyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1-yl}-6-trifluoromethyl-pyrimidine

-   -   0.5 g of 4-methyl-5-tert-butyl-4H-[1,2,4]triazole-3-thiol (2.92        mmol) were reacted with 1.07 g of        2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-trifluoromethyl-pyrimidine        (2.92 mmol) to yield 1.05 g of the title compound.

MS (ESI) m/z: 500.3 [M+H]⁺

c.282-tert-Butyl-4-{4-[3-(4-methyl-5-trifluoromethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1-yl}-6-ethyl-pyrimidinehydrochloride

-   -   0.36 g of 4-methyl-5-trifluoromethyl-4H-[1,2,4]triazole-3-thiol        (1.96 mmol) were reacted with 0.64 g        2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-ethyl-pyrimidine        (1.96 mmol) to yield 500 mg of the title compound.

MS (ESI) m/z: 472.2 [M+H]⁺

¹H-NMR (DMSO): δ [ppm] 14.1 (s, broad, 1H), 11.95 (s, broad, 1H), 7.0(s, 1H), 4.9 (m, broad, 1H), 4.45 (m, broad, 1H), 3.75 (m, broad, 1H),3.65 (s, 3H), 3.6 (m, broad, 3H), 3.4 (m, 3H), 3.3 (m, 2H), 3.15 (m,broad, 2H), 2.85 (m, 2H), 2.15 (m, 2H), 1.35 (s, 9H), 1.3 (m, 3H),

c.292-tert-Butyl-4-{4-[3-(4-methyl-5-ethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1-yl}-6-difluoromethyl-pyrimidinehydrochloride

-   -   0.619 g of 4-methyl-5-ethyl-4H-[1,2,4]triazole-3-thiol (4.32        mmol were reacted with 1.5 g of        2-tert-Butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-difluoromethyl-pyrimidine        (4.32 mmol), to yield 0.5 g of the title compound.

MS (ESI) m/z: 454.2 [M+H]⁺

¹H-NMR (DMSO): δ [ppm] 11.95 (s, 1H, broad), 10.2 (s, 1H, broad), 7.1(s, 1H), 6.8 (t, 1H, CHF2), 4.65 (s, 2H), 3.65 (s, 3H), 3.5-3.7 (m, 4H,broad), 3.45 (m, 2H), 3.2 (m, 2H), 2.95-3.2 (m, 4H, broad), 2.2 (m, 2H),1.25-1.4 (m, 12H)

The compounds II of examples c.30 to c.38 can be obtained by analogy tothe methods described in the examples c.1 or c.2:

c.302-tert-Butyl-4-{4-[3-(4-methyl-5-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1-yl}-6-(1-methylcycloproyl)-pyrimidinehydrochloride c.312-tert-Butyl-4-{4-[3-(4-methyl-5-(4-fluorophenyl)-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1-yl}-6-trifluoromethyl-pyrimidinehydrochloride c.322-tert-Butyl-4-{4-[3-(4-methyl-5-phenyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1-yl}-6-trifluoromethyl-pyrimidinehydrochloride c. 332-tert-Butyl-4-{4-[3-(4-methyl-5-(1-methylpyrrol-2-yl)-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]piperazin-1-yl}-6-trifluoromethyl-pyrimidinehydrochloride c.342-tert-Butyl-4-{4-[3-(4-methyl-5-cyclobutyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1-yl}-6-tert-butyl-pyrimidinehydrochloride c.352-tert-Butyl-4-{4-[3-(4-methyl-5-phenyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1-yl}-6-tert-butyl-pyrimidinehydrochloride c.362-tert-Butyl-4-{4-[3-(4-methyl-5-methoxymethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1-yl}-6-tert-butyl-pyrimidinehydrochloride c.372-tert-Butyl-4-{4-[3-(4-methyl-5-(1-methylpyrrol-2-yl)-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1-yl}-6-tert-butyl-pyrimidinehydrochloride c.382-tert-Butyl-4-{4-[3-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1-yl}-6-isopropyl-pyrimidinehydrochloride c-392-tert-Butyl-4-{4-[3-(1-methyl-1H-[1,2,4]triazole-3-sulfanyl)-propyl]-piperazin-1-yl}-6-trifluoromethyl-pyrimidinehydrochloride

-   -   ESI-MS: 444.25 [M+H]⁺

¹H-NMR (DMSO): δ [ppm] 11.7 (s, broad, 1H), 8.5 (s, 1H), 7.2 (s, 1H),3.8 (s, 3H), 3.45-3.7 (m, 4H), 3.1-3.2 (m, 4H), 3.0-3.1 (m, 2H), 2.1-2.2(m, 2H), 1.3 (s, 9H), 1.05 (m, 2H).

c-402,6-di-tert-Butyl-4-{4-[3-(2-methyl-1H-[1,2,4]triazole-3-sulfanyl)-propyl]-piperazin-1-yl}-pyrimidinehydrochloride

-   -   ESI-MS: 432.25 [M+H]⁺

¹H-NMR (DMSO): δ [ppm] 12.5 (s, broad, 1H), 12.15 (s, broad, 1H), 8.0(s, 1H), 6.9 (s, 1H), 5.0 (m, broad, 1H), 4.7 (m, broad, 1H), 3.75 (s,3H), 3.6-3.9 (several m, broad, 4H), 3.3 (m, 2H), 3.1-3.3 (m, 4H), 2.2(m, 2H), 1.4-1.5 (m, 18H).

c-412,6-di-tert-Butyl-4-{4-[3-(1H-[1,2,4]triazole-3-sulfanyl)-propyl]-piperazin-1-yl}-pyrimidine

-   -   ESI-MS: 418.2 [M+H]⁺

¹H-NMR (CDCl₃): δ [ppm] 7.9 (s, 1H), 6.3 (s, 1H), 3.8 (m, 4H), 3.2 (m,2H), 2.6-2.7 (m, 6H), 2.0-2.1 (m, 2H), 1.3 (s, 9H), 1.25 (s, 9H).

c-422-tert-Butyl-4-{4-[3-(4-methyl-1H-[1,2,4]triazole-3-sulfanyl)-propyl]-piperazin-1-yl}-6-cyclopentyl-pyrimidine

-   -   ESI-MS: 444.25 [M+H]⁺

¹H-NMR (CDCl₃): δ [ppm] 8.1 (s, 1H), 6.15 (s, 1H), 3.65 (m, 4H), 3.6 (s,3H), 3.3-3.4 (m, 2H), 2.9-3.0 (m, 1H), 2.45-2.6 (m, 6H), 1.9-2.1 (m,4H), 1.7-1.85 (m, 4H), 1.6-1.7 (m, 2H), 1.3 (s, 9H).

c-432,6-di-tert-Butyl-4-{4-[3-(1-methyl-1H-[1,2,4]triazole-3-sulfanyl)-propyl]-piperazin-1-yl}-pyrimidine

-   -   ESI-MS: 432.25 [M+H]⁺

¹H-NMR (CDCl₃): δ [ppm] 7.95 (s, 1H), 6.23 (s, 1H), 3.85 (s, 3H),3.6-3.7 (m, 4H), 3.1-3.2 (m, 2H), 2.5 (m, 6H), 1.95 (m, 2H), 1.3 (s,9H), 1.25 (s, 9H).

c-442-tert-Butyl-4-{4-[3-(1-methyl-1H-[1,2,4]triazole-3-sulfanyl)-propyl]-piperazin-1-yl}-6-propyl-pyrimidine

-   -   ESI-MS: 418.5 [M+H]⁺

II. Preparation of the compounds I Example 12,4-Di-tert-butyl-6-{4-[3-(4,5-dimethyl-4H-[1,2,4]triazole-3-sulfinyl)-propyl]-piperazin-1-yl}-pyrimidine

10 g of2,4-di-tert-butyl-6-{4-[3-(4,5-dimethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1-yl}-pyrimidin(18.01 mmol) were dissolved in 300 ml water. At room temperature, 9 mlof 2 N aqueous hydrochlorid acid (18.01 mmol) were added. The solutionwas cooled to 5° C. and 5.54 g (9.0 mmol) of oxone added in portions.After consumption of the starting material, the crude reaction productwas isolated and subjected to a silica gel chromatography with ethylacetate, ethyl acetate-methanol 15:1 to 8:1. Isolated were 1.16 g of2,4-di-tert-butyl-6-{4-[3-(4,5-dimethyl-4H-[1,2,4]triazole-3-sulfonyl)-propyl]-piperazin-1-yl}-pyrimidine(Example 4) and 6.5 g of2,4-di-tert-butyl-6-{4-[3-(4,5-dimethyl-4H-[1,2,4]triazole-3-sulfinyl)-propyl]-piperazin-1-yl}-pyrimidine.The latter product was dissolved in 10 ml of n-hexane and crystallizedovernight in the refrigerator to yield 5.6 g of the desired product.

ESI-MS: 462.3 [M+H]⁺

¹H-NMR (CDCl₃): δ [ppm] 6.25 (s, 1H), 3.85 (s, 3H), 3.5-3.7 (m, 6H),2.45-2.65 (m, 9H), 2.0-2.2 (m, 2H), 1.35 (s, 9H), 1.3 (s, 9H).

Example 22-tert-Butyl-4-cyclobutyl-6-{4-[3-(4-methyl-4H-[1,2,4]triazole-3-sulfonyl)-propyl]-piperazin-1-yl}-pyrimidine

38 mg were obtained as described for example 1.

ESI-MS: 462.3 [M+H]⁺

¹-NMR (CDCl₃): δ [ppm] 8.2 (s, 1H), 6.1 (s, 1H), 4.0 (s, 3H), 3.8 (m,2H), 3.6-3.7 (m, 4H), 3.4 (m, 1H), 2.45-2.6 (m, 6H), 2.1-2.35 (m, 6H),2.0 (m, 1H), 1.9 (m, 1H), 1.35 (s, 9H).

Example 32-tert-Butyl-4-cyclobutyl-6-{4-[3-(4-methyl-4H-[1,2,4]triazole-3-sulfinyl)-propyl]-piperazin-1-yl}-pyrimidine

550 mg were obtained as described for example 1.

ESI-MS: 446.3 [M+H]⁺

¹H-NMR (CDCl₃): δ [ppm] 8.25 (s, 1H), 6.1 (s, 1H), 4.0 (s, 3H), 3.5-3.7(m, 6H), 3.4 (m, 1H), 2.45-2.6 (m, 6H), 2.25 (m, 4H), 2.15 (m, 1H),1.95-2.1 (m, 2H), 1.9 (m, 1H), 1.35 (s, 9H).

Example 42,4-Di-tert-butyl-6-{4-[3-(4,5-dimethyl-4H-[1,2,4]triazole-3-sulfonyl)-propyl]-piperazin-1-yl}-pyrimidine

1.16 g were obtained from the silica gel chromatography of Example 1.

ESI-MS: 478.3 [M+H]⁺

¹H-NMR (CDCl₃): δ [ppm] 6.25 (s, 1H), 3.85 (s, 3H), 3.8 (m, 2H), 3.65(m, 4H), 2.45-2.65 (m, 9H), 2.1-2.2 (m, 2H), 1.2-1.4 (18H).

Example 52-tert-Butyl-4-{4-[3-(5-ethyl-4-methyl-4H-[1,2,4]triazole-3-sulfinyl)-propyl]-piperazin-1-yl}-6-propyl-pyrimidinehydrochloride

200 mg were obtained as described for example 1. The hydrochloride saltwas formed by addition of HCl/diethyl ether and careful evaporation ofthe solvent.

ESI-MS: 462.5 [M+H]⁺

¹H-NMR (d₆-DMSO): δ [ppm] 14.3 (s, broad, 1H), 12.1 (s, broad, 1H), 7.15(s, 1H), 5.05 (m, broad, 1H), 4.5 (m, broad, 1H), 3.85 (m, broad, 1H),3.85 (s, 3H), 3.5-3.75 (m, 5H), 3.3 (m, 2H), 3.2 (m, 2H), 2.95 (m, 2H),2.85 (m, 2H), 2.25 (m, 2H), 1.7 (m, 2H), 1.45 (9H), 1.3 (t, 3H), 0.95(t, 3H).

Example 62-tert-Butyl-4-{4-[3-(4,5-dimethyl-4H-[1,2,4]triazole-3-sulfinyl)-propyl]-piperazin-1-yl}-6-(1-methyl-cyclopropyl)-pyrimidine

144 mg were obtained as described for example 1.

ESI-MS: 460.4 [M+H]⁺

¹H-NMR (CDCl₃): δ [ppm] 6.3 (s, 1H), 3.85 (s, 3H), 3.5-3.7 (m, 6H),2.45-2.65 (m, 9H), 2.0-2.2 (m, 2H), 1.4 (s, 3H), 1.35 (m, 2H), 1.3 (s,9H), 0.7 (m, 2H).

Example 72-tert-Butyl-4-{4-[3-(4,5-dimethyl-4H-[1,2,4]triazole-3-sulfinyl)-propyl]-piperazin-1-yl}-6-trifluoromethyl-pyrimidinehydrochloride

360 mg were obtained as described for example 1. The hydrochloride saltwas formed by addition of HCl/diethyl ether and careful evaporation ofthe solvent.

ESI-MS: 474.1 [M+H]⁺

¹H-NMR (DMSO): δ [ppm] 11.8 (s, very broad, 1H), 7.2 (s, 1H), 4.7 (m,very broad, 2H), 3.8 (s, 3H), 3.45-3.7 (m, broad, 6H), 3.25 (m, broad,2H), 3.1 (m, broad, 2H), 2.5 (s, 3H), 2.25 (m, 2H), 1.3 (s, 9H).

Example 82-tert-Butyl-4-{4-[3-(4,5-dimethyl-4H-[1,2,4]triazole-3-sulfinyl)-propyl]-piperazin-1-yl}-6-propyl-pyrimidinehydrochloride

100 mg were obtained as described for example 1. The hydrochloride saltwas formed by addition of HCl/diethyl ether and careful evaporation ofthe solvent.

ESI-MS: 448.5 [M-1-H]⁺

¹H-NMR (DMSO): δ [ppm] 14.15 (s, very broad, 1H), 12.05 (s, very broad,1H), 7.15 (s, 1H), 5.0 (m, broad, 1H), 4.2-4.7 (m, broad, 1H), 3.85 (m,broad, 1H), 3.8 (s, 3H), 3.45-3.75 (m, broad, 5H), 3.3 (m, broad, 2H),3.2 (m, broad, 2H), 2.9 (m, broad, 2H), 2.5 (s, 3H), 2.25 (m, 2H), 1.7(m, 2H), 1.4 (s, 9H), 0.95 (t, 3H).

Example 92-Di-tert-butyl-6-{4-[3-(4,5-dimethyl-4H-[1,2,4]triazole-3-sulfonyl)-propyl]-piperazin-1-yl}-6-propyl-pyrimidine

30 mg were obtained as described for example 1.

Example 102-tert-Butyl-4-{4-[3-(4,5-dimethyl-4H-[1,2,4]triazole-3-sulfonyl)-propyl]-piperazin-1-yl}-6-(1-methyl-cyclopropyl)-pyrimidine

24 mg were obtained as described for example 1.

ESI-MS: 476.1 [M+H]⁺

Example 112-tert-Butyl-4-{4-[3-(4,5-dimethyl-4H-[1,2,4]triazole-3-sulfonyl)-propyl]-piperazin-1-yl}-6-trifluoromethyl-pyrimidine

21.9 mg were obtained as described for example 1.

ESI-MS: 490.1 [M+H]⁺

Example 122-tert-Butyl-4-{4-[3-(5-ethyl-4-methyl-4H-[1,2,4]triazole-3-sulfonyl)-propyl]-piperazin-1-yl}-6-propyl-pyrimidine

19.3 mg were obtained as described for example 1.

ESI-MS: 478.5 [M+H]⁺

Example 13 Enantiomer #1 of2,4-Di-tert-butyl-6-{4-[3-(4,5-dimethyl-4H-[1,2,4]triazole-3-sulfinyl)-propyl]-piperazin-1-yl}-pyrimidine

Chiral separation of 100 mg racemic of2,4-di-tert-butyl-6-{4-[3-(4,5-dimethyl-4H-[1,2,4]triazole-3-sulfinyl)-propyl]-piperazin-1-yl}-pyrimidine(example 1) (0.5 μg/ml) was performed on a Chiracel OD column using aseluent a mixture containing n-hexane/ethanol/trifluoroacetic acid(8:2:0.01) to yield 16 mg of enantiomer-1 and 28 mg of enantiomer-2(example 14).

Example 14 Enantiomer #2 of2,4-di-tert-butyl-6-{4-[3-(4,5-dimethyl-4H-[1,2,4]triazole-3-sulfinyl)-propyl]-piperazin-1-yl}-pyrimidine

28 mg enantiomer-2 was obtained from the chiral separation of2,4-di-tert-butyl-6-{-4-[3-(4,5-dimethyl-4H-[1,2,4]triazole-3-sulfinyl)-propyl]-piperazin-1-yl}-pyrimidine(example 1) as described above.

Example 152-tert-Butyl-4-(4-{3-[5-(4-fluoro-phenyl)-4-methyl-4H-[1,2,4]triazole-3-sulfinyl]-propyl}-piperazin-1-yl)-6-trifluoromethyl-pyrimidine

1.3 g were obtained as described for example 1.

ESI-MS: 554.2 [M+H]⁺

¹H-NMR (CDCl₃): δ [ppm] 7.65 (m, 2H), 7.25 (m, 2H), 6.6 (s, 1H), 3.95(s, 3H), 3.7 (m, 6H), 2.6 (m, 2H), 2.55 (m, 4H), 2.05-2.25 (m, 2H), 1.3(s, 9H).

Example 162-tert-Butyl-4-(4-{3-[5-(4-fluoro-phenyl)-4-methyl-4H-[1,2,4]triazole-3-sulfonyl]-propyl}-piperazin-1-yl)-6-trifluoromethyl-pyrimidinehydrochloride

166 mg were obtained as described for example 1. The hydrochloride saltwas formed by addition of HCl/diethyl ether and careful evaporation ofthe solvent.

ESI-MS: 570.2 [M+H]⁺

¹H-NMR (DMSO): δ [ppm] 11.5 (s, very broad, 1H), 7.85 (m, 2H), 7.45 (m,2H), 7.2 (s, 1H), 4.65 (m, very broad, 2H), 3.9 (m, 2H), 3.85 (s, 3H),3.5-3.6 (m, broad, 4H), 3.25 (m, broad, 2H), 3.1 (m, broad, 2H), 2.3 (m,2H), 1.3 (s, 9H).

Example 172,4-Di-tert-butyl-6-{4-[3-(4-methyl-4H-[1,2,4]triazole-3-sulfonyl)-propyl]-piperazin-1-yl}-pyrimidine

The title compound was obtained as described for example 1

ESI-MS: 464.2 [M+H]⁺

¹H-NMR (CDCl₃): δ [ppm] 8.2 (s, 1H), 6.25 (s, 1H), 4.0 (s, 3H), 3.8 (m,2H), 3.65 (m, 4H), 2.5-2.6 (several m, 6H), 2.1-2.2 (m, 2H), 1.35 (s,9H), 1.3 (s, 9H).

Example 182,4-Di-tert-butyl-6-{4-[3-(4-methyl-4H-[1,2,4]triazole-3-sulfinyl)-propyl]-piperazin-1-yl}-pyrimidine

The title compound was obtained as described for example 1

ESI-MS: 448.2 [M+H]⁺

¹H-NMR (CDCl₃): δ [ppm] 8.2 (s, 1H), 6.25 (s, 1H), 4.0 (s, 3H), 3.55-3.7(m, 6H), 2.6 (m, 2H), 2.5 (m, 4H), 2.15 (m, 1H), 2.05 (m, 1H), 1.3 (s,9H), 1.25 (s, 9H).

Example 192-tert-Butyl-4-{4-[3-(1-methyl-1H-[1,2,4]triazole-3-sulfonyl)-propyl]-piperazin-1-yl}-6-trifluoromethyl-pyrimidinehydrochloride

1-Methyl-1H-[1,2,4]triazole-3-thiol was purchased from Prosyntest,Estonia.

The title compound was obtained as described for example 1

ESI-MS: 476.1 [M+H]⁺

¹H-NMR (d₆-DMSO): δ [ppm] 11.65 (s, broad, 1H), 8.85 (s, 1H), 7.2 (s,1H), 4.35-4.85 (several m, broad, 3H), 4.0 (s, 3H), 3.6 (m, 2H), 3.5-3.6(m, 3H), 3.25 (m, 2H), 3.0-3.15 (m, 2H), 2.2 (m, 2H), 1.3 (s, 9H).

Example 202,4-Di-tert-butyl-6-{4-[3-(2-methyl-2H-[1,2,4]triazole-3-sulfonyl)-propyl]-piperazin-1-yl}-pyrimidinehydrochloride

2-Methyl-1H-[1,2,4]triazole-3-thiol was purchased.

The title compound was obtained as described for example 1

ESI-MS: 464.2 [M+H]⁺

¹H-NMR (d₆-DMSO): δ [ppm] 12.1 (s, broad, 1H), 8.3 (s, 1H), 6.8 (s,broad, 1H), 4.25-5.1 (several m, broad, 4H), 4.2 (s, 3H), 3.9 (m, 2H),3.45-3.8 (several m, 2H), 3.25 (m, 2H), 3.15 (m, broad, 2H), 2.2-2.3 (m,2H), 1.4 (s, broad, 18H).

Example 212-tert-Butyl-4-{4-[3-(1-methyl-1H-[1,2,4]triazole-3-sulfinyl)-propyl]-piperazin-1-yl}-6-trifluoromethyl-pyrimidinehydrochloride

1-Methyl-1H-[1,2,4]triazole-3-thiol was purchased from Prosyntest,Estonia.

The title compound was obtained as described for example 1

ESI-MS: 460.1 [M+H]⁺

¹H-NMR (d₆-DMSO): δ [ppm] 11.55 (s, broad, 1H), 8.8 (s, 1H), 7.2 (s,1H), 4.5-5.0 (several m, broad, 2H), 4.0 (s, 3H), 3.4-3.6 (several m,4H), 3.3 (m, 2H), 3.25 (m, 2H), 3.1 (m, 2H), 2.15 (m, 2H), 1.3 (s, 9H).

Example 22

2,4-Di-tert-butyl-6-{4-[3-(1H-[1,2,4]triazole-3-sulfonyl)-propyl]-piperazin-1-yl}-pyrimidine1H-[1,2,4]triazole-3-thiol was purchased.

The title compound was obtained as described for example 1

ESI-MS: 450.2 [M+H]⁺

¹H-NMR (d₆-DMSO): δ [ppm] 8.9 (s, 1H), 6.45 (s, 1H), 3.6 (m, 4H), 3.5(m, 2H), 2.4 (m, 6H), 1.85 (m, 2H), 1.2-1.35 (2s, 18H).

Example 232-tert-Butyl-4-{4-[3-(4-methyl-1H-[1,2,4]triazole-3-sulfonyl)-propyl]-piperazin-1-yl}-6-isopropyl-pyrimidine

The title compound was obtained as described for example 1

ESI-MS: 450.2 [M+H]⁺

¹H-NMR (d₆-DMSO): δ [ppm] 8.85 (s, 1H), 6.4 (s, 1H), 3.9 (s, 3H), 3.7(m, 2H), 3.6 (m, 4H), 3.3 (s, 3H), 2.75 (m, 1H), 2.4 (m, 4H), 1.9 (m,2H), 1.3 (s, 9H), 1.2 (d, 6H).

Example 242-tent-Butyl-4-{4-[3-(4-methyl-1H-[1,2,4]triazole-3-sulfonyl)-propyl]-piperazin-1-yl}-6-cyclopentyl-pyrimidine

The title compound was obtained as described for example 1

ESI-MS: 476.3 [M+H]⁺

¹H-NMR (CDCl₃): δ [ppm] 8.2 (s, 1H), 6.15 (s, 1H), 4.0 (s, 3H), 3.8 (m,2H), 3.6 (m, 4H), 2.95 (m, 1H), 2.55 (m, 1H), 2.45-2.6 (m, 5H), 2.2 (m,2H), 1.95 (m, 2H), 1.8 (m, 4H), 1.65 (m, 2H), 1.3 (s, 9H).

Example 252-tert-Butyl-4-{4-[3-(4-methyl-1H-[1,2,4]triazole-3-sulfinyl)-propyl]-piperazin-1-yl}-6-cyclopentyl-pyrimidine

The title compound was obtained as described for example 1

ESI-MS: 460.14 [M+H]⁺

¹H-NMR (CDCl₃): δ [ppm] 8.2 (s, 1H), 6.1 (s, 1H), 4.0 (s, 3H), 3.6 (m,6H), 2.95 (m, 1H), 2.55 (m, 1H), 2.45-2.6 (m, 5H), 2.15 (m, 1H), 2.05(m, 1H), 1.95 (m, 2H), 1.8 (m, 4H), 1.65 (m, 2H), 1.3 (s, 9H).

Example 262-tert-Butyl-4-{4-[3-(4-methyl-1H-[1,2,4]triazole-3-sulfonyl)-propyl]-piperazin-1-yl}-6-propyl-pyrimidine

The title compound was obtained as described for example 1

ESI-MS: 450.2 [M+H]⁺

¹H-NMR (CDCl₃): δ [ppm] 8.2 (s, 1H), 6.1 (s, 1H), 4.0 (s, 3H), 3.8 (m,2H), 3.6-3.7 (m, 4H), 2.45-2.6 (m, 8H), 2.15 (m, 2H), 1.7 (m, 2H), 1.35(s, 9H), 0.95 (t, 3H).

Example 272,6-di-tert-Butyl-4-{4-[3-(1-methyl-1H-[1,2,4]triazole-3-sulfonyl)-propyl]-piperazin-1-yl}-pyrimidine

1-Methyl-1H-[1,2,4]triazole-3-thiol was purchased from Prosyntest,Estonia.

The title compound was obtained as described for example 1

ESI-MS: 464.2 [M+H]⁺

¹H-NMR (CDCl₃): δ [ppm] 8.2 (s, 1H), 6.25 (s, 1H), 4.05 (s, 3H),3.55-3.65 (m, 4H), 3.4-3.5 (m, 2H), 2.4-2.55 (m, 6H), 2.0-2.1 (m, 2H),1.3 (s, 9H), 1.25 (s, 9H).

Example 282-tert-Butyl-4-{4-[3-(1-methyl-1H-[1,2,4]triazole-3-sulfinyl)-propyl]-piperazin-1-yl}-6-propyl-pyrimidinehydrochloride

1-Methyl-1H-[1,2,4]triazole-3-thiol was purchased from Prosyntest,Estonia.

The title compound was obtained as described for example 1

ESI-MS: 434.2 [M+H]⁺

¹H-NMR (DMSO): δ [ppm] 14.3 (s, broad, 1H), 12.1 (s, broad, 1H), 8.8 (s,1H), 7.15 (s, 1H), 5.0 (m, broad, 1H), 4.5 (m, broad, 1H), 4.0 (s, 3H),3.05-3.9 (several m, broad, 10H), 2.9-3.0 (m, 2H), 2.1-2.2 (m, 2H), 1.7(m, 2H), 1.45 (s, 9H), 0.9-1.0 (m, 3H).

Example 292-tert-Butyl-4-{4-[3-(1-methyl-1H-[1,2,4]triazole-3-sulfonyl)-propyl]-piperazin-1-yl}-6-propyl-pyrimidine

The title compound was obtained as described for example 1

ESI-MS: 450.5 [M+H]⁺

¹H-NMR (CDCl₃): δ [ppm] 8.2 (s, 1H), 6.1 (s, 1H), 4.05 (s, 3H),3.55-3.65 (m, 4H), 3.4-3.5 (m, 2H), 2.4-2.6 (m, 8H), 2.0-2.1 (m, 2H),1.7 (m, 2H), 1.3 (s, 9H), 0.9-1.0 (t, 3H).

Example 302,6-di-tert-Butyl-4-{4-[3-(1-methyl-1H-[1,2,4]triazole-3-sulfinyl)-propyl]-piperazin-1-yl}-pyrimidinehydrochloride

The title compound was obtained as described for example 1

¹H-NMR (DMSO): δ [ppm] 8.8 (s, 1H), 6.75 (s, broad, 1H), 4.65 (m, broad,2H), 4.0 (s, 3H), 3.5-3.9 (several m, broad, 8H), 3.2-3.35 (m, 4H),3.0-3.2 (m, 2H), 2.1-2.2 (m, 2H), 1.2-1.5 (broad, 18H).

Example 312-tert-butyl-6-{4-[3-(1H-[1,2,4]triazole-3-sulfonyl)-propyl]-piperazin-1-yl}-6-(1-methyl)cyclopropyl-pyrimidine

The title compound was obtained as described for example 1

Example 32

(S)-2-tert-Butyl-4-{4-[3-(1-methyl-1H-[1,2,4]triazole-3-sulfinyl)-propyl]-piperazin-1-yl}-6-propyl-pyrimidine

The title compound was obtained as described for example 1

ESI-MS: 434.25 [M+H]⁺

Example 33(R)-2-tert-Butyl-4-{(4-[3-(1-methyl-1H-[1,2,4]triazole-3-sulfinyl)-propyl]-piperazin-1-yl}-6-propyl-pyrimidine

The title compound was obtained as described for example 1

ESI-MS: 434.25 [M+H]⁺

The compounds of examples 34 to 164 given in tables 1, 2, 3 or 4 were orcan be prepared by analogy to the methods described in the previousexamples.

TABLE 1 Compounds of the formula I, wherein Ar is Ar-1. Example R¹ X R²34 cyclopropyl SO trifluoromethyl 35 cyclopropyl SO₂ trifluoromethyl 36cyclobutyl SO trifluoromethyl 37 cyclobutyl SO₂ trifluoromethyl 38phenyl SO trifluoromethyl 39 phenyl SO₂ trifluoromethyl 40 methoxymethylSO trifluoromethyl 41 methoxymethyl SO₂ trifluoromethyl 42trifluoromethyl SO trifluoromethyl 43 trifluoromethyl SO₂trifluoromethyl 44 N-methyl-pyrrol-2-yl SO trifluoromethyl 45N-methyl-pyrrol-2-yl SO₂ trifluoromethyl 46 cyclopropyl SO tert-butyl 47cyclopropyl SO₂ tert-butyl 48 cyclobutyl SO tert-butyl 49 cyclobutyl SO₂tert-butyl 50 phenyl SO tert-butyl 51 phenyl SO₂ tert-butyl 52methoxymethyl SO tert-butyl 53 methoxymethyl SO₂ tert-butyl 54trifluoromethyl SO tert-butyl 55 trifluoromethyl SO₂ tert-butyl 56N-methyl-pyrrol-2-yl SO tert-butyl 57 N-methyl-pyrrol-2-yl SO₂tert-butyl 58 ethyl SO trifluoromethyl 59 ethyl SO₂ trifluoromethyl 60 H(S)—SO trifluoromethyl 61 H (S)—SO propyl 62 H (S)—SO isopropyl 63 H(S)—SO difluoromethyl 64 H (S)—SO cyclobutyl 65 H (S)—SO cyclopentyl 66H (R)—SO trifluoromethyl 67 H (R)—SO propyl 68 H (R)—SO isopropyl 69 H(R)—SO difluoromethyl 70 H (R)—SO cyclobutyl 71 H (R)—SO cyclopentyl 72H SO₂ trifluoromethyl 73 H SO₂ propyl 74 H SO₂ difluoromethyl 75 H SO₂cyclobutyl 76 H (S)—SO trifluoromethyl 77 H (S)—SO difluoromethyl 78 H(S)—SO Tert-butyl 79 H (S)—SO propyl

TABLE 2 Compounds of the formula I, wherein Ar is Ar-2 and R^(1a) is H.Example R¹ X R² 80 H (S)—SO cyclobutyl 81 H (S)—SO isopropyl 82 H (R)—SOtrifluoromethyl 83 H (R)—SO difluoromethyl 84 H (R)—SO Tert-butyl 85 H(R)—SO propyl 86 H (R)—SO cyclobutyl 87 H (R)—SO isopropyl 88 methyl SO₂trifluoromethyl 89 methyl SO₂ propyl 90 methyl SO₂ difluoromethyl 91methyl SO₂ cyclobutyl 92 methyl (S)—SO trifluoromethyl 93 methyl (S)—SOdifluoromethyl 94 methyl (S)—SO Tert-butyl 95 methyl (S)—SO propyl 96methyl (S)—SO cyclobutyl 97 methyl (S)—SO isopropyl 98 methyl (R)—SOtrifluoromethyl 99 methyl (R)—SO difluoromethyl 100 methyl (R)—SOTert-butyl 101 methyl (R)—SO propyl 102 methyl (R)—SO cyclobutyl 103methyl (R)—SO isopropyl

TABLE 3 Compounds of the formula I, wherein Ar is Ar-2 and R^(1a) ismethyl. Example R¹ X R² 104 H SO₂ difluoromethyl 105 H SO₂ cyclobutyl106 H (S)—SO trifluoromethyl 107 H (S)—SO difluoromethyl 108 H (S)—SOTert-butyl 109 H (S)—SO propyl 110 H (S)—SO cyclobutyl 111 H (S)—SOisopropyl 112 H (R)—SO trifluoromethyl 113 H (R)—SO difluoromethyl 114 H(R)—SO Tert-butyl 115 H (R)—SO propyl 116 H (R)—SO cyclobutyl 117 H(R)—SO isopropyl 118 methyl SO₂ trifluoromethyl 119 methyl SO₂ propyl120 methyl SO₂ difluoromethyl 121 methyl SO₂ cyclobutyl 122 methyl(S)—SO trifluoromethyl 123 methyl (S)—SO difluoromethyl 124 methyl(S)—SO Tert-butyl 125 methyl (S)—SO propyl 126 methyl (S)—SO cyclobutyl127 methyl (S)—SO isopropyl 128 methyl (R)—SO trifluoromethyl 129 methyl(R)—SO difluoromethyl 130 methyl (R)—SO Tert-butyl 131 methyl (R)—SOpropyl 132 methyl (R)—SO cyclobutyl 133 methyl (R)—SO isopropyl

TABLE 4 Compounds of the formula I, wherein Ar is Ar-3 and R^(1a) ismethyl. Example R¹ X R² 134 H SO₂ difluoromethyl 135 H SO₂trifluoromethyl 136 H SO₂ cyclobutyl 137 H (S)—SO trifluoromethyl 138 H(S)—SO difluoromethyl 139 H (S)—SO Tert-butyl 140 H (S)—SO propyl 141 H(S)—SO cyclobutyl 142 H (S)—SO isopropyl 143 H (R)—SO trifluoromethyl144 H (R)—SO difluoromethyl 145 H (R)—SO Tert-butyl 146 H (R)—SO propyl147 H (R)—SO cyclobutyl 148 H (R)—SO isopropyl 149 methyl SO₂trifluoromethyl 150 methyl SO₂ propyl 151 methyl SO₂ difluoromethyl 152methyl SO₂ cyclobutyl 153 methyl (S)—SO trifluoromethyl 154 methyl(S)—SO difluoromethyl 155 methyl (S)—SO Tert-butyl 156 methyl (S)—SOpropyl 157 methyl (S)—SO cyclobutyl 158 methyl (S)—SO isopropyl 159methyl (R)—SO trifluoromethyl 160 methyl (R)—SO difluoromethyl 161methyl (R)—SO Tert-butyl 162 methyl (R)—SO propyl 163 methyl (R)—SOcyclobutyl 164 methyl (R)—SO isopropyl

III. Examples of Galenic Administration Forms

A) Tablets

-   -   Tablets of the following composition are pressed on a tablet        press in the customary manner:        -   40 mg of substance from Example 4        -   120 mg of corn starch        -   13.5 mg of gelatin        -   45 mg of lactose        -   2.25 mg of Aerosil® (chemically pure silicic acid in            submicroscopically fine dispersion)        -   6.75 mg of potato starch (as a 6% paste)

B) Sugar-Coated Tablets

-   -   20 mg of substance from Example 4    -   60 mg of core composition    -   70 mg of saccharification composition    -   The core composition consists of 9 parts of corn starch, 3 parts        of lactose and 1 part of 60:40 vinylpyrrolidone/vinyl acetate        copolymer. The saccharification composition consists of 5 parts        of cane sugar, 2 parts of corn starch, 2 parts of calcium        carbonate and 1 part of talc. The sugar-coated tablets which had        been prepared in this way are subsequently provided with a        gastric juice-resistant coating.

IV. Biological Investigations 1. Receptor Binding Studies

-   -   The substance to be tested was either dissolved in        methanol/Chremophor® (BASF-AG) or in dimethyl sulfoxide and then        diluted with water to the desired concentration.

Dopamine D₃ Receptor:

-   -   The assay mixture (0.250 ml) was composed of membranes derived        from ˜10⁸ HEK-293 cells possessing stably expressed human        dopamine D₃ receptors, 0.1 nM [¹²⁵I]-iodosulpride and incubation        buffer (total binding) or, in addition, test substance        (inhibition curve) or 1 μM spiperone (nonspecific binding). Each        assay mixture was run in triplicate.

The incubation buffer contained 50 mM tris, 120 mM NaCl, 5 mM KCl, 2 mMCaCl₂, 2 mM MgCl₂ and 0.1% bovine serum albumin, 10 μM quinolone and0.1% ascorbic acid (prepared fresh daily). The buffer was adjusted to pH7.4 with HCl.

Dopamine D_(2L) Receptor:

The assay mixture (1 ml) was composed of membranes from ˜10⁶ HEK-293cells possessing stably expressed human dopamine D_(2L) receptors (longisoform) and 0.01 nM [¹²⁵I] iodospiperone and incubation buffer (totalbinding) or, in addition, test substance (inhibition curve) or 1 μMhaloperidol (nonspecific binding). Each assay mixture was run intriplicate.

-   -   The incubation buffer contained 50 mM tris, 120 mM NaCl, 5 mM        KCl, 2 mM CaCl₂, 2 mM MgCl₂ and 0.1% bovine serum albumin. The        buffer was adjusted to pH 7.4 with HCl.

Measurement and Analysis:

-   -   After having been incubated at 25° C. for 60 minutes, the assay        mixtures were filtered through a Wathman GF/B glass fiber filter        under vacuum using a cell collecting device. The filters were        transferred to scintillation viols using a filter transfer        system. After 4 ml of Ultima Gold® (Packard) have been added,        the samples were shaken for one hour and the radioactivity was        then counted in a Beta-Counter (Packard, Tricarb 2000 or        2200CA). The cpm values were converted into dpm using a standard        quench series and the program belonging to the instrument.    -   The inhibition curves were analyzed by means of iterative        nonlinear regression analysis using the Statistical Analysis        System (SAS) which is similar to the “LIGAND” program described        by Munson and Rodbard.    -   In these tests, the compounds according to the invention exhibit        very good affinities for the D₃ receptor (K_(i)<10 nM,        frequently <5 nM) and bind selectively to the D₃ receptor.    -   The results of the binding tests are given in table 2, along        with results obtained using two reference compounds A and B        deemed representative of previously-described triazole        compounds. The relative D₃ and D₂ affinities demonstrate the        high selectivity of the compounds of the invention for the D₃        receptor.

2. Determination of the Concentration of compounds in Plasma and BrainFollowing Dosing of Compounds in Animals

-   -   Male Sprague-Dawley rats were used in this study (2 to 4 per        experiment). The animals were fasted overnight prior to dosing        and throughout the duration of the study but were permitted        water ad libitum.    -   Each rat received a 10 mg/kg (5 mL/kg) dose orally by gavage. At        0.5, 3 and 8 hours after drug administration, three animals were        put under deep anesthesia using isoflurane and euthanized by        bleeding (cardiac puncture) under deep isoflurane anesthesia.        EDTA blood samples and brain tissue will be collected from each        rat. Upon collection, the samples were promptly placed in an ice        bath, and within 2 hours after sample collection, the blood was        centrifuged at about 4° C. The resulting brain and plasma        samples were placed in clean glass tubes and stored in a freezer        until analysis.    -   The plasma samples were assayed for parent compound using        appropriate liquid chromatography—mass spectrometry procedures.        The results for compounds I are given in tables 2, and        illustrate the high brain concentrations attainable with the        compounds of the invention.

TABLE 5 Properties of Compounds of the Formula I where Ar is Ar-1Selectivity Brain level Ex. # R¹ n R² K_(i) D₃ [nM][K_(i)(D₂)/K_(i)(D₃)] [ng/g] 1 methyl 1 tert-butyl (racemate) 19.5 261670 2 hydrogen 2 cyclobutyl 52 14 n.d. 3 hydrogen 1 cyclobutyl 12 44n.d. 4 methyl 2 Tert-butyl 6.1 34 1920 5 ethyl 1 n-propyl 38 37 n.d. 6methyl 1 1-methyl-cyclopropyl 28.7 20 n.d. 8 methyl 1 n-propyl 56 33n.d. 9 methyl 2 n-propyl 18.3 45 n.d. 10 methyl 2 1-methyl-cyclopropyl7.8 37 n.d. 12 ethyl 2 n-propyl 12.8 55 n.d. 13 methyl 1 tert-butyl n.d.n.d. n.d. (enantiomer 1) 14 methyl 1 tert-butyl n.d. n.d. n.d.(enantiomer 2) 15 4-fluoro- 1 trifluoromethyl 12.6 100  n.d. phenyl 164-fluoro- 2 trifluoromethyl 17.7 56 n.d. phenyl

TABLE 6 Binding properties of Compounds of the Formula I, Examples 17 to31 Selectivity Brain level Exp. # k_(i) D₃ [nM] [K_(i)(D₂)/K_(i)(D₃)][ng/g] 17 5.95 53 n.d. 18 25 17 n.d. 19 32 17 n.d. 20 26.2 8 n.d. 2116.6 18 n.d. 22 47.4 19 n.d. 23 59.8 49 n.d. 24 7.5 20 n.d. 25 23.3 30n.d. 26 44.6 33 n.d. 27 9.7 24 n.d. 28 9.9 158 n.d. 29 20.3 59 n.d. 303.5 51 n.d. 31 22.6 37 n.d. n.d. = not determined Exp.: Example

In the receptor binding studies described in IV.1 the compounds II ofexamples c.3, c.4, c.6, c.7, c.12, c.15, c.16, c.17, c18, c20, c.21,c.27, c.28 and c.29 showed K_(i) D₃ values below 5 nM and selectivities[K_(i)(D₂)/K_(i)(D₃)] exceeding 50.

The brain levels determined for compounds c.9, c.16, c.17 and c.19 bythe method described in IV.2 exceed 200 ng/g.

TABLE 7 Properties of Compounds of the Formula IIa Brain level Exp. # D₃[nM] D₂/D₃ [ng/g] c.4 1.5 96 290 c.7 1.2 115 n.d. c.11 1.7 470 840 c.122.4 143 780 c.13 1.3 157 n.d. c.14 1.5 135 n.d. c.15 2 364 1410  c.160.65 237 n.d. c.17 0.9 293 n.d. c.18 2.9 134 n.d. c.45 3.9 21 c.46 3.7525 c.48 1.2 4 c.50 0.46 18 c.53 1.1 5 c.54 1.46 88 n.d. not determinedExp.: Example

1. Triazole compounds of the formula I

wherein n is 1 or 2; Ar is a C-bound 1,2,4-triazol radical which carriesa radical R¹ on the remaining carbon atom and a radical R^(1a) on one ofthe nitrogen atoms; R¹ is hydrogen, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₁-C₄alkoxymethyl, fluorinated C₁-C₆ alkyl, fluorinated C₃-C₆ cycloalkyl,fluorinated C₁-C₄ alkoxymethyl, phenyl or 5- or 6-membered heteroaryl,wherein phenyl and heteroaryl may be unsubstituted or substituted by 1,2, 3 or 4 radicals R^(a) selected independently of each other fromhalogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₄ alkoxy-C₁-C₄-alkyl,fluorinated C₁-C₄ alkyl, CN, NO₂, OR³, NR³R⁴, C(O)NR³R⁴, O—C(O)NR³R⁴,SO₂NR³R⁴, COOR⁵, SR⁶, SOR⁶, SO₂R⁶, O—C(O)R⁷, COR⁷ or C₃-C₅cycloalkylmethyl, wherein phenyl and heteroaryl may also carry a phenylgroup or an aromatic 5- or 6-membered C-bound heteroaromatic radical,comprising 1 nitrogen atom as ring member and 0, 1, 2 or 3 furtherheteroatoms, independently of each other, selected from O, S and N,wherein the last two mentioned radicals may carry 1, 2, 3 or 4 of theaforementioned radicals R^(a); R^(1a) is hydrogen or C₁-C₄-alkyl; R² isC₁-C₆ alkyl, C₃-C₆ cycloalkyl, fluorinated C₁-C₆ alkyl or fluorinatedC₃-C₆ cycloalkyl; R³, R⁴, R⁵, R⁶, and R⁷ independent of each other areH, C₁-C₆ alkyl, optionally substituted with OH, C₁-C₄ alkoxy or phenyl,C₁-C₄ haloalkyl or phenyl, which may carry 1, 2 or 3 radicals selectedfrom the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, NR^(3a)R⁴a, CN,C₁-C₂ fluoroalkyl and halogen, wherein R^(3a) and R^(4a) are independentof each other H, C₁-C₆ alkyl, optionally substituted with OH, C₁-C₄alkoxy or phenyl, C₁-C₄ haloalkyl or phenyl, which may carry 1, 2 or 3radicals selected from the group consisting of C₁-C₆ alkyl, C₁-C₆alkoxy, amino, NH(C₁-C₄ alkyl) and N(C₁-C₄ alkyl)₂, R⁴ may also be aradical COR⁸, wherein R⁸ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxy orphenyl, which may carry 1, 2 or 3 radicals selected from the groupconsisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, NR³R⁴, CN, C₁-C₂ fluoroalkyland halogen, R³ and R⁴ may together with the nitrogen atom to which theyare bound form a N-bound 5 or 6 membered saturated heterocyle, which maycomprise an oxygen atom or an additional nitrogen atom as a ring memberand which may carry 1, 2, 3 or 4 C₁-C₆ alkyl groups and thephysiologically tolerated acid addition salts of these compounds.
 2. Acompound as claimed in claim 1, wherein Ar is a radical of the formulaAr-1,

wherein # denotes the binding position to the Sulfur atom of the groupS(O)_(n) and R¹ is as defined in claim
 1. 3. A compound as claimed inclaim 1, wherein Ar is a radical of the formula Ar-2,

wherein # denotes the binding position to the Sulfur atom of the groupS(O)_(n) and R¹ and R^(1a) are as defined in claim
 1. 4. A compound asclaimed in claim 1, wherein Ar is a radical of the formula Ar-3,

wherein # denotes the binding position to the Sulfur atom of the groupS(O)_(n) and R¹R¹ and R^(1a) are as defined in claim
 1. 5. A compound asclaimed in any of claim 1, 2, 3 or 4, wherein R¹ is selected from thegroup consisting of hydrogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl, C₁-C₄alkoxymethyl and trifluoromethyl.
 6. A compound as claimed in any ofclaim 1, 2, 3 or 4, wherein R¹ is hydrogen or methyl.
 7. A compound asclaimed in any of claim 1, 2, 3 or 4, wherein R² is selected from thegroup consisting of C₃-C₄ alkyl or fluorinated C₁-C₂ alkyl.
 8. Acompound as claimed in any of claim 1, 2, 3 or 4, wherein R² is selectedfrom the group consisting of n-propyl, isopropyl and tert-butyl.
 9. Acompound as claimed in any of claim 1, 2, 3 or 4, wherein R² istert-butyl.
 10. A compound as claimed in claim 9, wherein R¹ ishydrogen.
 11. A compound as claimed in claim 9, wherein R¹ is methyl.12. A compound as claimed in any of claim 1, 2, 3 or 4, wherein R² isselected from the group consisting of trifluoromethyl anddifluoromethyl.
 13. A compound as claimed any of claim 1, 2, 3 or 4,wherein R² is trifluoromethyl.
 14. A compound as claimed in claim 13,wherein R¹ is hydrogen.
 15. A compound as claimed in claim 13, whereinR¹ is methyl.
 16. A compound as claimed in any of claim 1, 2, 3 or 4,wherein R² is C₃-C₄ cycloalkyl or fluorinated C₃-C₄ cycloalkyl.
 17. Acompound as claimed in claim 16, wherein R¹ is hydrogen.
 18. A compoundas claimed in claim 16, wherein R¹ is methyl.
 19. A pharmaceuticalcomposition comprising at least one compound as claimed in any of claim1, 2, 3 or 4 together with at least one physiologically acceptablecarrier or auxiliary substance.
 20. A method for treating a medicaldisorder of the central nervous system susceptible to treatment with adopamine D₃ receptor antagonist or a dopamine D₃ agonist, said methodcomprising administering an effective amount of at least one compound asclaimed in any of claim 1, 2, 3 or 4 to a subject in need thereof. 21.The method as claimed in claim 20, wherein the medical disorder isschizophrenia.
 22. Triazole compounds of the formula IIa

wherein Ar is a C-bound 1,2,4-triazol radical which carries a radical R¹on the remaining carbon atom and a radical R¹⁸ on one of the nitrogenatoms; R¹ is selected from the group consisting of C₂-C₆-alkyl,fluorinated C₁-C₆-alkyl, C₃-C₆ cycloalkyl, C₁-C₄ alkoxymethyl,fluorinated C₃-C₆ cycloalkyl and fluorinated C₁-C₄ alkoxymethyl; R^(1a)is hydrogen or C₁-C₄ alkyl; and R² is C₁-C₆ alkyl or fluorinated C₁-C₆alkyl; and the physiologically tolerated acid addition salts of thesecompounds.
 23. The compound as claimed in claim 22, wherein Ar is aradical of the formula Ar-1,

wherein # denotes the binding position to the Sulfur atom of the groupS(O)_(n) and R¹ is as defined in claim
 22. 24. A compound as claimed inclaim 22, wherein Ar is a radical of the formula Ar-2,

wherein # denotes the binding position to the Sulfur atom of the groupS(O)_(r), and R¹ and R^(1a) are as defined in claim
 22. 25. A compoundas claimed in claim 22, wherein Ar is a radical of the formula Ar-3,

wherein # denotes the binding position to the Sulfur atom of the groupS(O)_(n) and R¹R¹ and R^(1a) are as defined in claim
 22. 26. A compoundas claimed in any of claim 22, 23, 24 or 25, wherein R¹ is selected fromthe group consisting of C₂-C₄-alkyl, trifluoromethyl, C₃-C₅ cycloalkyland C₁-C₄ alkoxymethyl.
 27. A compound as claimed in any of claim 22,23, 24 or 25, wherein R² is selected from the group consisting of C₃-C₄alkyl or fluorinated C₁-C₂ alkyl.
 28. A compound as claimed in any ofclaim 22, 23, 24 or 25, wherein R² is selected from the group consistingof n-propyl, isopropyl and tert-butyl.
 29. A compound as claimed in anyof claim 22, 23, 24 or 25, wherein R² is tert-butyl.
 30. A compound asclaimed in any of claim 22, 23, 24 or 25, wherein R² is selected fromthe group consisting of trifluoromethyl and difluoromethyl.
 31. Acompound as claimed in any of claim 22, 23, 24 or 25, wherein R² istrifluoromethyl.
 32. A pharmaceutical composition comprising at leastone compound as claimed in any of claim 22, 23, 24 or 25 together withat least one physiologically acceptable carrier or auxiliary substance.33. A method for treating a medical disorder of the central nervoussystem susceptible to treatment with a dopamine D₃ receptor antagonistor a dopamine D₃ agonist, said method comprising administering aneffective amount of at least one compound as claimed in claim any ofclaim 22, 23, 24 or 25 to a subject in need thereof.
 34. The method asclaimed in claim 33, wherein the medical disorder is schizophrenia.